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CA2209134A1 - Tricyclic retinoids, methods for their production and use - Google Patents

Tricyclic retinoids, methods for their production and use

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Publication number
CA2209134A1
CA2209134A1 CA002209134A CA2209134A CA2209134A1 CA 2209134 A1 CA2209134 A1 CA 2209134A1 CA 002209134 A CA002209134 A CA 002209134A CA 2209134 A CA2209134 A CA 2209134A CA 2209134 A1 CA2209134 A1 CA 2209134A1
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CA
Canada
Prior art keywords
methyl
hexa
hexahydro
compound
tetramethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002209134A
Other languages
French (fr)
Inventor
Youssef L. Bennani
Steven K. White
Chan Kou Hwang
Luc J. Farmer
Alex M. Nadzan
Jonathan J. Hebert
Stacie S. Canan Koch
Beth Ann Badea
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ligand Pharmaceuticals Inc
Original Assignee
Individual
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Filing date
Publication date
Priority claimed from US08/475,514 external-priority patent/US5770382A/en
Priority claimed from US08/475,397 external-priority patent/US5770383A/en
Priority claimed from US08/472,127 external-priority patent/US5770378A/en
Application filed by Individual filed Critical Individual
Publication of CA2209134A1 publication Critical patent/CA2209134A1/en
Abandoned legal-status Critical Current

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
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    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
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Abstract

Tricyclic retinoids having activity for retinoic acid receptors and/or retinoid X receptors are provided. Also provided are pharmaceutical compositions incorporating such tricyclic retinoid compounds and methods for their therapeutic use.

Description

DOCKET NO. CA 02209134 1997-06-27 016-0019A.W~

TRICYCLIC RETINOIDS~ MET~ODS
FOR l H~!;11~ PRODUCTION AND USE

Field of the Invention The present invention relates to retinoid compounds having activity for retinoic acid receptors and retinoid X receptors, and to methods for the production and therapeutic use of such compounds.

Back~round of the Invention The vitarnin A metabolite, retinoic acid, has long been recognized to induce a broad spectrum of biological effects. In addition, a variety of structural analogues of retinoic acid have been synthesized that also have been found to be bioactive. Some? such as Retin-A~
and Accutane~, have found utility as therapeutic agents for the treatment of various pathological conditions. In addition, synthetic retinoids have been found to mimic many of the pharmacological actions of retinoic acid.
Medical professionals have become very interested in the therapeutic applications of retinoids. Among their uses approved by the FDA is the treatment of severe forms of acne and psoriasis. A large body of evidence also exists that these compounds can be used to arrest and, to an extent, reverse the effects of skin damage arising from prolonged exposure to the sun. Other evidence exists that these compounds may be useful in the treatment and prevention of a variety of cancerous and pre-cancerous conditions, such as melanoma, cervical cancer, some forms of leukemia, oral leukoplakia and basal and squamous cell carcinomas. Retinoids have also shown an ability to be efficacious in treating and preventing diseases of the eye, cardiovascular system, immune system, skin, respiratory and digestive tracts, and as agents to f~cili~te wound healing and modulate programmed cell death (apoptosis).
Major insight into the molecular mechanism of retinoic acid signal transduction was gained in 1988, when a member ofthe steroid/thyroid hormone intracellular receptor superfamily was shown to transduce a retinoic acid signal. Evans, Science, 240:889-95 (1988); Giguere et al., Nature, 330:624-29 (1987); Petkovich ef al., Nafure, 330: 444-50 (1987). It is now known that retinoids regulate the activity oftwo distinct intracellular receptor subfamilies; the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

(RXRs), incl~l~ling their isoforms, RARa, ,~, y and RXRoc, ,~, ~. In this regard, an endogenous low-molecular-weight ligand which modulates the transcriptional activity of the RARs is all-trans-retinoic acid (ATRA), while an endogenous ligand for the R~Rs is 9-cis retinoic acid (9-cis). Heyman et al., Cell, 68:397-406 (1992) and Levin et al. Nature, 355:359-61 (1992).
Although both the RARs and RXRs respond to ATRA in vivo, due to the in vivo conversion of some of the ATRA to 9-cis, the receptors differ in several important aspects.
First, the RARs and RXRs are significantly divergent in primary structure (e.g., the ligand binding domains of RARa and RXRoc have only 27% amino acid identity). These structural differences are reflected in the dirre,el~ relative degrees of responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids. In addition, distinctly di~l-elll patterns of tissue distribution are seen for RARs and RXRs. For example, in contrast to the RARs, which are not expressed at high levels in the visceral tissues, RXRo~
mRNA has been shown to be most abundant in the liver, kidney, lung, muscle and intestine.
Finally, the RARs and R~Rs have dirrel e~L target gene specificity. For example, response elements have recently been identified in the cellular retinal binding protein type II (CRBPII) and Apolipoprotein AI genes which confer responsiveness to RXR, but not RAR.
Furthermore, RAR has also been recently shown to repress RXR-mediated activationthrough the CRBPII RXR response element (Manglesdorf et al., Cell, 66:555-61 (1991)).
These data indicate that two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay.
In view of the related, but clearly distinct, nature of these receptors, retinoids which are more selective for the RAR subfamily or the RXR subfamily would be of great value for selectively controlling processes mediated by one or more of the RAR or RXR isoforms, and would provide the capacity for independent control of the physiologic processes mediated by the RARs or R~Rs. In addition, pan-agonist retinoids that activate one or more isoforms of both the RARs and RXRs would also be valuable for controlling processes mediated by both of these subfamilies of retinoid receptors. Furthermore, retinoids which prerer~"~ially affect one or more but not all of the receptor isoforms also offer the possibility of increased therapeutic eff1cacy and reduced side effect profiles when used for therapeutic applications.

DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

Various tricyclic compounds, the majority of which are beta-substituted on the Cring, have been disclosed to have retinoid activity, incllltling those compounds disclosed in H. Kagechika et al., "Retinobenzoic Acids. 2. Structure-Activity Relationship of Chalcone-4-carboxylic Acids and Flavone-4'-carboxylic Acids", 32 J. Med. C.hem., 834 (1989); H.
5 Kagechika et al., "Retinobenzoic Acids. 3. Structure-Activity Relationships of Retinoidal Azobenzene-4-carboxylic Acids and Stilbene-4-carboxylic Acids", 32 J. Med. Chem., 1098 (1989); H. Kagechika et al., "Retinobenzoic Acids. 4. Conformation of Aromatic Amides with Retinoidal Activity. Importance of h ans-Amide Structure for the Activity", 32 J. Med.
Chem., 2292 (1989); M.I. Dawson et al., "Effect of Structural Modifications in the C7-C11 10 Region of the Retinoid Skeleton on Biological Activity in a Series of Aromatic Retinoids", 32 J. Med. Chem., 1504 (1989) and U.S. Patent Nos. 4,831,052, 4,874,747, 4,925,979, 5,004,730, 5,124, 473 and Re 33,533.

DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Summa~ of the Invention The present invention provides novel tricyclic retinoid compounds that have selective activity on RARs and RXRs or pan-agonist activity on one or more of each of the RAR and RXR isoforms. The present invention also provides pharmaceutical compositions 5 incorporating these novel tricyclic compounds and methods for the therapeutic use of such compounds and pharmaceutical compositions.
These and various other advantages and features of novelty which characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better underst~n~ling of the invention, its advantages, and objects 10 obtained by its use, reference should be had to the accompanying drawings and descriptive matter, in which there is illustrated and described preferred embodiments of the invention.
. De~lnitions In accordance with the present invention and as used herein, the following termsare defined with the following me~ning.~, unless explicitly stated otherwise.
The term alkyl refers to straight-chain, branched-chain, cyclic structures, and combinations thereof.
The term aryl refers to an optionally substituted six-membered aromatic ring.
The term heteroaryl refers to an optionally substituted five-membered or six-membered heterocyclic ring conl~ining one or more heteroatoms selected from the group 20 consisting of oxygen, nitrogen and sulfur.
The terms retinoid or retinoids refer to compound(s) that bind and/or activate one or more retinoid receptors~ thereby affecting the transcriptional activity of a target gene to which the activated receptor and compound complex binds.
The term pan-agonist refers to a retinoid that activates at least one member of both 25 the RAR subfamily (i.e., RARa, RAR,~, or RARy) and the RXR subfamily (i.e., R~
RXR,~, or R~R~). Preferably such pan-agonist retinoids activate all members of both the RAR and RXR subfamilies of retinoid receptors.

DOCK~ET NO.CA 02209134 1997-06-27 016-0019A.WO

Detailed Description of Embodiments of the Invention In accordance with a first aspect of the present invention, we have developed tricyclic retinoid compounds of the formulae: -~,R14 R1 ~R2 IR10 Z ~ ~ ~ )n R3 R4 Rg (I) OR

R1~ ~R2 ¦

10R3 R4 Rg (I~
OR

R1 ~R2 ~ )n ~ ,;~ R1 0 R3 R4 Rg (III) OR

=
DOCK~ET NO. CA 02209l34 l997-06-27 016-0019A.WO

R~
m(RZ~ b Z'~7~R3n - R3 R4 p~g (IV) OR

R1 ~R2 R10 IR21 R2 ~ J~ ;~/IR

(R28~ ~ Z"~R8R3 R3 F~4 Rg (V) OR

~R14 ~?~I/R6 m( R2 ~ ~Y,~, ~ Z ~ R8R

R3 R4 Rg 0 (VI) wherein, Rl through R4 each independently are hydrogen, a Cl - C6 alkyl, or a C7 - C15 arylalkyl;
R5 through R8 each independently are hydrogen, a Cl - C6 alkyl, or at least two of R5 through R8 taken together are a C3 - C6 cycloalkyl;

DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Rg and Rlo each independently are hydrogen, a Cl - C6 alkyl, F, Cl, Br, NR11R12, NO2 or OR13, where Rll and R12 each independently are hydrogen, a Cl - Cg alkyl, a C7 -Cls arylalkyl, a Cl - Cg acyl, provided that only one of Rll or R12 can be acyl, or Rll and R12 taken together are a C3 - C6 cycloalkyl, and where R13 is hydrogen or a Cl - Cg alkyl or 5 a C7 - Cls arylalkyl;
R14 represents:

~COR15 ~, COR15 ~ ~COR15 ~ ~ COR15 ~--COR15 ~V ~, COR15 where Rls is OR16 or NR17Rlg, with R16 being hydrogen, a Cl - C6 alkyl or a C7 - Cls arylalkyl, and with R17 and Rlg each independently being hydrogen, a C1 - C6 alkyl, a C7 -C1s arylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C3 - C6 cycloalkyl, provided that R1g must be hydrogen when R17 is aryl or hydroxyaryl, R1g is a Cl - Cs alkyl, and A is O, S or NR20, where R20 is a hydrogen, Cl - C6 alkyl or a C7 - Cls 1 5 arylalkyl;
R21 represents:

COR15 ~ ~ COR15 ~\~ COR15 /~A~ ~ COR15 ~V ~ COR15 DOCKJETNO. CA 02209134 1997-06-27 016-0019A.WO

where Rls, Rlg, and A have the same definitions given above;
R26 through R2g each independently are hydrogen or a Cl - C6 alkyl, or taken - together then one each of R26 and R27 or 1~28 and R2g respectively, form a carbonyl group;
X and Y each independently represent C, O, S, N, SO or SO2, provided, however, 5 that when X or Y are O, S, SO or S02, then either Rl and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of Rl and R2 or R3 and R4 respectively, do not exist;
Z is O, S, CR22R23 or NR24, where R22 through R24 each independently are hydrogen or a Cl - C6 alkyl or R22 and R23 taken together are a C3 - C6 cycloalkyl;
W is N or CR2~, where R2s is hydrogen or a Cl - C6 alkyl;
V is C or N, provided, however, that when V is N, then no double bond exists adjacent to V;
G is C or N, provided G cannot be C when W is C;
M is C, O, S, NR24, where R24 is hydrogen, a C 1 - C6 alkyl, or does not exist if a double bond exists adjacent to N;
m is 0 or 1 carbon atoms;
n is 0, 1 or 2 carbon atoms;
q is 1 or 2 carbon atoms;
the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then one each of Rs and R6 or R7 and R8 respectively do not exist; and the wav,v lines represent olefin bonds that are either in the cis (Z) or trans ~) configuration.
The compounds of the present invention also include all pharmaceutically acceptable salts, as well as esters and amides. Preferably, such salts, esters and amides, will be forrned at the Rls and R16 positions. As used in this disclosure, pharm~ceutically acceptable salts include, but are not limited to: pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and DOCK~ET NO. CA 02209134 1997-06-27 016-00 1 9A.WO

tris(hydoxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.
The compounds of the present invention are particularly useful in the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, 5 infl~mm~tory and non-infl~mm~tory acne, psoriasis, ichthyoses and other k~ ion and hyperproliferative disorders ofthe skin, er~m~ atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-. microbial, as skin pigment~tion agents and to treat and reverse the effects of age and photodamage to the skin. The compounds are also useful for the prevention and treatment of 10 cancerous and pre-cancerous conditions, in~ll1(1ing, prçm~lip;n~nt and m~ ;n~nt hyperproliferative diseases such as cancers ofthe breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and Iymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the tre~tmt?nt of Kaposis sarcoma. In addition, the present compounds can be used as 15 agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in -~ the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of restenosis and as an agent to increase the level of circ~ ting tissue plasminogen activator 20 (TPA). Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various infl~mm~tory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS), improper pituitary function, 25 incll1tling insufflcient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil~, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunoctim~ nt.s, modulation of organ transplant 30 rejection and facilitation of wound he~ling, including modulation of chelosis. It will also be understood by those skilled in the art that the retinoid compounds of the present invention DOCK~ETNO. CA 02209134 1997-06-27 016-0019A.WO

will prove usefill in any therapy in which retinoids, including RAR selective retinoids, R~
selective retinoids, and pan-agonist retinoids will find application.
Furthermore, it will be understood by those skilled in the art that the compounds of the present invention, including pharrnaceutical compositions and formulations cont~ining these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immlln- logical modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
Representative retinoids of the present invention include, without limitation, ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-l-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-
2,3-5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]napthalen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-2,3-5,6,7,8-hexahydro-5,5,8,8,-tetramethyl-cyclopenta[b]naphthalen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-1,2,3,6,7,8-hexahydro-1, 1,3,3-tetramethylcycopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoate; (2E,4E)-3 -methyl-6-[(Z)- 1 ,2,3,6,7,8-hexahydro- 1,1,3 ,3-tetra-cyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-(2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-hexamethylbenzo[b]-chromen-4-ylidene)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-l-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracen-l-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracen-l-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(Z)-2,3,5,6,7,8-hexahydro-
3,5,5,8,8-pentamethyl-cyclopenta[b]naphthalen-1-ylidene]hexa-2,4,-dienoic acid; (2E,4E)-3-methyl-6-[(Z)-3,5,6,7-tetrahydro-5,5,7,7-tetramethyl-2H-5-indacen-1 -ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

575,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]naphthalen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(E)-2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]naphthalen-l-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]-5-ylidene]hexa-2,4-dienoic acid; ethyl (2Z,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoate; (2Z,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-(E)-[4,4,6,6,9,9-hexamethyl-1,2,3,4,5,6,7,8-octahydroanthracen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E,6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoate; ethyl (2E,4E,6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoate; ethyl (2Z,4E,6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoate; (2Z, 4E, 6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoic acid;
(2E,4E)-3-methyl-6-[(E)-3,5,6,7-tetrahydro-5,5,7,7-tetramethyl-2H-5-indacen-1 -ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen- 1 -ylidene]hexa-2,4-dienoate; (2E,4E)-3 -methyl-6-[(E)-53,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; (2Z,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(E) 2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-ylidene]hexa-2,4-dienoic acid; (2Z,4E)-3-methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-yliden]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(E)-,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(3,4,5,6,7,8 -hexahydro-5,5,8,8-tetramethylanthracen- 1 -yl)hexa-2,4-dienoate; (2E,4E)-3 -methyl-6-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen- 1 -yl)hexa-2,4-dienoic acid;
(3E,5E)-3-methyl-6-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-3,5-dienoic acid; ethyl (2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

tetramethylanthracen-l-yl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethyl-anthracen-1-yl)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(1,2,3,5,6,7,8-heptahydro-5,5,8,8-tetramethylcyclopenta[b]napthalen-1-yl)hexa-2,4-dienoate; (2E,4E)-3 -methyl-6- 1,2, 3 (S, 6, 7, 8-heptahydro-5, 5, 8, 8-tetramethyl-cyclopenta[b]naphthalen-1-yl]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[1,2,3,4,7,8,9, iO-octahydro-l, 1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4 dienoate; (2E,4E)-3-methyl-6-[1,2,3,4,7,8,9, 10-octahydro-1, 1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4-dienoic acid; ethyl (2Z,4E)-3-methyl-6-[1,2,3,4,7,8,9, 10-octahydro-1, 1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4-dienoate; (2Z,4E)-3-methyl-6-[1,2,3,4,7,8,9, 10-octahydro-1, 1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4-dienoic acid; (2Z,4E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro- 1,1 ,4,4-tetramethyl-6H-naphthocycloheptan- 1 0-yl]hexa-2,4-dienoic acid;
(2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-2,2-dimethylpyran-4-yl]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-pyran-4-yl]hexa-2,4-dienoic acid; (2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b )-pyran-4-yl]hexa-2,4-dienoic acid; (+)-(2E,4E)-3-methyl-6-(1 ,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoic acid; (-)-(2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen- 1 -yl)hexa-2, 4-dienoic acid; methyl (2E)-3 -methyl-6 -(1, 2, 3, 4, 6, 7, 8, 9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)hex-2-enoate; (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)hex-2-enoic acid; (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)hex-2-enoic acid;
(2E,4E)-3-methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl- lH-cyclopenta[a]naphthalen-3-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-lH-cyclopenta[a]naphthalen-3-yl]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-lH-cyclopenta[a]naphthalen-3-yl)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-1 ,2,3 ,4,7,8,9-heptahydro-7,7,9,9-tetramethylcyclopenta[f~naphthalen-4-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethylcyclopenta[f~naphthalen-4-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(7,7,10, 10-tetramethyl-2,3,4,5,7,8,9, 10-octahydronaphtho[2,3-6]-azepinyl)hexa-2,4-DOCKET NO. CA 02209134 1997-06-27 dienoate; (2E,4E)-3-methyl-6-[7,7, 10,10-tetramethyl-2,3,4,5,7,8,9, 10-octahydronaphtho[2,3-6]azepinyl)hexa-2,4-dienoic acid; ethyl 3-methyl-6-(3,4,6,7,8,9-hexahydro -6, 6, 9, 9-tetramethyl-2H-benzo [g] quinolin- 1 -yl)hexa-2, 4-dienoate; (2E, 4E)-3 -methyl-6-[3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1 -yl)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-oxo-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl(2,3)naphthyl [b]piperidin-1-yl]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-oxo-6-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-yl)hexa-2,4-dienoic acid;
ethyl (2E,4E)-3-methyl-6-oxo-6-[(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl)benzo[~indol-1-yl]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-oxo-6-[(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl)benzo-[f~-indol-1-yl]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylbenzo[f~indol-1-yl]-hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylbenzo[f~indol-1-yl]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(7,7,10,10-tetrahydro-5,5,8,8-tetramethyl)benzo[f~quinolin-
4-yl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(1,2,3,4,7, 8,9,1 0-octahydro-7,7, 10,10-tetramethylbenzo[l:~quinolin-4-yl)hexa-2,4-dienoic acid; (2E, 4E)-3-methyl-6-[(Z)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl(2,3-b-pyran-4-ylidene]hexa-2,4-dienoic acid;
(2E,4E)-3-methyl-[(E)-3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethyl-2H-anthracen-1-ylidene]-hexa-2,4,-dienoic acid; Ethyl (2E,4E)-3-methyl-6-[(Z)-N-acyl-3,4,5,6,7,8-hexahydro-10-amino-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate;(2E,4E)-3 -methyl-6-[(Z)-N-acyl-3 ,4, 5, 6, 7, 8 -hexahydro- 1 0-amino-5, 5, 8, 8 -tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(E)l-ethyl-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydro-lH-benzo[g]quinolin-4-ylidene]-hexa-2,4,dienoic acid; 4-(5-carboxy-penta-2E-4E-dieneylidene)-6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinolin-1-carboxylic acid tert butyl ester; (2E,4E)-3-methyl-(6,6,9,9-tetramethyl-2,3,6,9-tetrahydro-naphtho[2,3-b]-[1,4]oxazin-4-yl)-hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-oxo-6-(6,6,9,9-tetrahydro-2,3,6,9-tetrahydro-naphtho[2,3-b][1 ,4]oxazin-4-yl)-hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-(6-ethyl-1,9,9-trimethyl-7-oxo-2,3,6,7,8,9-hexahydro-lH-pyrido[2,3-g]quinolin-4-ylidene)-hexa-2,4-dienoic acid; E-4-(6,6,9,9-Tetramethyl-1,2,6,7,8,9-hexahydro-2H-anthracen-1-yl)hydrazonebenzoic acid; E-4[1,2,3,4-Tetrahydro-6,6,9,9-tetramethylnaphto(2,3)pyran-4-yl(2-hydrazono)benzoic acid; and DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

(2E,4E) 6-(6-ethyl- 1,9,9-trimethyl-2,3,6,9-tetrahydro- 1 H-pyrido [2,3 -g] quinolin-4-ylidene)-3-methyl-hexa-2,4-dienoic acid.
The compounds of the present invention can be obtained by modification of the compounds disclosed or by a total synthesis approach, by techniques known to those skilled
5 in the art. In this regard, the synthesis of the compounds of the present invention often follow established retinoid synthesis schemes and techniques as described in M.I. Dawson and W.H. Okamura, "Chemistry and Biology of Synthetic Retinoids", Chapters 3, 8, 14 and 16, CRC Press, Inc., Florida (1990); M.I. Dawson and P.D. Hobbs, The Synthetic C.hemistry of Retinoids, In Chapter 2: "The Retinoids, Biology, Chemistry and Medicine", M.B. Sporn et al., Eds. (2nd ed.), Raven Press, New York, New York, pp. 5-178 (1994); R.S.H. Liu and A. E. Asato, "Photochemistry and Synthesis of Stereoisomers of Vitamin A," 40 Tetrahedron, 1931 (1984); 43 C.ancerRes., 5268 (1983); 15 E~r. J. Med. C.hem., 9 (1980);
and U.S. Patent Nos. 4,326,055 and 4,578,498, the disclosures of which are herein incorporated by reference. The sequence of steps of the general schemes of synthesizing the 15 compounds of the present invention are shown below. In addition, more detailed and illustrative synthetic schemes for specific compounds of the present invention will be found in the Examples included herein.

[rest of page left purposely blank]

DOCk~ETNO. CA 02209134 1997-06-27 0 16-00 19A.WO

Scheme I: Svnthesis of Compounds of Structure (n:

[~X ~ ~ (EtO)2P(O)CH2CN

m /Y\~\Z~ 7) n NaH or BuLi/THF

~ ~' ~ ~ :'~) n R3 R4 9 R3 R4 Rg 3 (minor) 4 (major) 1~l (EtO)2P
1. DIBAL >=~ 1. DIBAL
2nB5ULj, 5 R/ COR15 2n.B5Lj, DMPU/THF DMPUJrHF

R150C~
l l ~COR15 R1 9 ~ R1 9 \ ~ ~ RR6 ~ 2 R ~ l m/Y\/~ F 8 n m /y\~\~\ F 8 n
6 7 The tricyclic derivatives of the present invention, that is compounds of generalstructures 6 and 7, may be prepared in accordance with reaction Scheme I. The starting materials for this sequence, ketones of general structure 1, may be prepared from the DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

appropriately substituted octahydroanthracene by oxidation with chromium trioxide in acetic acid at ambient temperature or with chromium trioxide in methylene chloride/pyridine at 0~C.
Further, in accordance with this sequence of reactions tricyclic ketones of general structure 1 are condensed with the sodium or lithium salt of diethyl cyanomethylphosphonate in THF at 5 reduced temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide a mixture of the cis-cyano olefins 3 as the minor products and the trans-cyano olefins 4 as the major products. The olefinic products may be separated by silica gel flash column chromatography.
The cis-cyano olefins 3 are reduced with DIBAL at -78~C to give the intermediate10 enals. The solvent to be used in the reduction includes methylene chloride, hexanes, and THF. The product of the DIBAL reduction, the enal, is reacted with the lithium salt of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double bond isomers) in THF at reduced temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide the tricyclic derivatives of general structure 6 where R1 5 is ethyl. The olefination reaction is preferably conducted in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). The acids and salts derived from structure 6 are readily obtainable from the corresponding esters. The ethyl esters may be hydrolyzed in an alkanol solvent at ambient temperature with about a three molar excess of base, for example, potassium hydroxide. Alternatively, the ethyl esters may be hydrolyzed in THF/water or acetone/water 20 at ambient temperature with, for example, excess lithium hydroxide. The hydrolysis solution is acidified and the hydrolysate recovered by conventional means to give as the major product the (2E, 4E)-Z-ylidene tricyclic carboxylic acid derivatives of structure 6 where R1s is OH. The minor (2Z, 4E)-Z-ylidene geometric isomers of general structure 6, by-products of the olefination reaction, are readily isolated by silica gel chromatography of the 25 hydrolysate mixture.
In an analogous fashion, in accordance with reaction Scheme I, the trans-cyano olefins 4 are transformed into the (2E, 4E)-E-ylidene and (2Z, 4E)-E-ylidene tricyclic derivatives 7 where R1s is ethoxy and OH.

DOCK~ET NO. CA 02209134 1997-06-27 0 16-0019A.WO

Scheme II: S~nthesis of ComPounds of Structure (1):

EtOO~
Rl /~R~, = Rs 1. I l _ OEt ~X~ 5 m /Y\~z~R7) 2. CO2, E~OH or m( y/~ ~R7) ¦ TranS-i5om~r R3 R4 Rg R8 TsOH /EtOH / \ Rg R8 8 Major 9 minor Rl50~
1. DIBAL-H
~ \ 2. MnO2 Rlg ~ OHC~

R, ~ ~R6 5,nBuLi, THF, DMPU ~J'~.

/ \/~\ Rs n R/ \R R9 An alternative means for making the tricyclic derivatives of general structure 6 is in accordance with reaction Scheme II. Tricyclic ketones 1 are treated with ethoxy ethynyl magnesium bromide in T~ at 0~C to ambient temperature. The resl-lting propargylic alcohols are isolated by typical extractive means, dissolved in ethanol and treated with carbon dioxide (gas) or, alternatively, a catalytic amount ofp-toluensulfonic acid and/or camphor sulfonic acid to provide a mixture of the cis-olefinic esters 8 as the major product and the trans-olefinic esters of general structure 9 as the minor product. The olefinic products may be separated by silica gel flash colurnn chromatography.
The cis-olefinic esters of general structure 8 are reduced with DIBAL at -~/8~C to give the intermediate allylic alcohol. The solvent to be used in the reduction includes methylene chloride, hexanes, and THF. The product ofthe DIBAL reduction, the allylic alcohol, is oxidized with m~ng~nese dioxide in methylene chloride at ambient temperature to provide the cis-enals of general structure 10. The enals are converted into tricyclic DOCK~ETNO. CA 02209134 1997-06-27 0 16-00 19A.WO

derivatives of general structure 6 by cond~n~tion with the phosphonate 5 by the same processes as those employed in the preparation process of Scheme I to produce tricycles of general structure 6 and 7.

5 Scheme m Synthesis of ComPounds of Structure (I):

\X~R6 1 NaBH4 MeOH ~ ~ r ~ 1 ~/R
~/~\ ~R7 ) 2. Ph3P-HBr ( Y ~\~/J\ ~R7 ) nBuLi, THF
OHC-Q--COR~5 ~COR15 1 2b 12a nBuLi, THF/DMPU
~COR1 5 ~R~g /COR~5 RR ) n [~X' ~ ~) n
7 13 ~3 ~A3 A

DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

An alternative means for making the tricyclic derivatives of general structure 7 is in accordance with reaction Scheme III The starting material for this sequence, ketones 1, may be prepared from the appropriately substituted octahydroanthracenes by oxidation with chromium trioxide in acetic acid at ambient temperature or with chromium trioxide in 5 methylene chloride/pyridine at low temperature. The tricyclic ketones are reduced with sodium borohydride in methanol at low temperature and the resultant benzylic alcohols are reacted with triphenylphosphine hydrobromide in methanol at elevated temperature to provide phosphonium salts of general structure 11. Compounds 12a where R1 5 is ethyl and Rlg is methyl used for the following olefination reaction are prepared from commercially 10 available (triphenylphosphoranylidene)acetaldehyde and ethyl 3-methyl-4-oxo-crotonate A
Horner-Wadsworth-Emmons olefination reaction in THF at reduced temperatures with the lithium salt of compounds 11 and compounds of general structure 12a provide the tricyclic derivatives 7 where R1s is ethoxy. The olefination reaction is preferably conducted in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). The acids and 15 salts derived from general structure 7 are readily obtainable from the corresponding esters by the same processes as those employed in the previously described process for tricycles of general structure 6.
Compounds of general structure 13 may be prepared from the lithium salt of the phosphonium bromide of general structure 11 and aldehyde of general structure 12b by the 20 same olefination processes as those employed for the preparation of a compound of general structure 7. The acids and salts derived from general structure 13 are readily obtainable from the corresponding esters by the same processes as those employed in the preparation process of Scheme I for tricycles of general structures 6 and 7.

[rest of page left purposely blankl DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Scheme 1~ Svnthesis of Compounds of Structure (I):

s (E~O)zP(O)CH2CN ~f~ NC

7) NaH or nBuLi/THF ~ ,~R7) ~' R n 14 15 maior 16 minor ~' ~ ~) / \
R3 R4 Rg R3 R4 An alternative means for making the intermediate tricyclic derivatives of general structure 4 is in accordance with reaction Scheme IV. The bicyclic ketones 14 are condensed with the sodium or lithium salt of diethyl cyanomethylphosphonate in THF at reduced temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide a mixture of the frans-cyano olefins 15 as the major products and the cis-cyano olefins 16 as the minor products. The olefinic products may be separated by silica gel flash column chromatography.
The tricyclic derivatives of general structure 4 are prepared by ~ minllm trichloride catalyzed Friedel-Crafts alkylation/cyclization of 2,5-dichloro-2,5-dialkylhexanes 17 with the bicycles of general structure 15 and 16 in dichlorometh~ne at ambient temperature.

[rest of page left purposely blank]

DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Scheme V: Svnthesis of ComPounds of Structure (II):

COOMe R (MeO~ P(O~C~COOMe [~ 1 DIBAL-H

/ \ R3 n nBuLi, THF m( ~ R7) 1 18 ~ CO~5 I~R19 CHO J
R1 / IZ~ R1 /~ ~

mYJ\~z~--R7) ' m( ~ z,~R7) / \ 3 n nBuLi, DMPU/THF /\ R~ n R3 R4 Rg R3 R4 Rg The tricyclic derivatives of general structure 20 can be prepared in accordance with reaction Scheme V. Tricyclic ketones 1 are condensed with the lithium salt of trimethyl phosphonoacetate in THF at elevated temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide the ~,y-unsaturated esters 18. The esters are reduced with one equivalent of DIBAL in methylene chloride at -78~C to provide aldehydes of general structure 19. The aldehydes are converted into tricyclic derivatives 20 by condensation with the phosphonates 5 by the same processes as those employed in the process of Scheme I to produce tricycles of general structure 6 and 7.

[rest of page left purposely blankl DOC~ETNO. CA 02209134 1997-06-27 016-0019A.WO

Scheme VI: Synthesis of Comnounds of Structure (II):

CN ,CN

X~ ~ ¢,~RR6 1 l2, ~d-C ~ Rs ~R7 ) / \ 1 R8 n ~' /
R1s--\ / 1. DIBAL
Il ~ 2. 5, nBuLi, DMPU/THF

m ~ ~ n The tricyclic derivatives of structure 22 can be prepared in accordance with reaction 5 Scheme VI. The previously described unsaturated nitriles 4 (see process for reaction Scheme I) are reduced by catalytic hydrogenation over 10% pall~ m-on-carbon in ethyl acetate to provide the saturated nitriles 21. In accordance with the processes employed in reaction Scheme I, the nitriles can be transformed into the tricyclic derivatives of general structure 22.

[rest of page left purposely blank DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Scheme VII: SYnthesis of ComPounds of Structure (II):

Scheme Vll.

COOMe ~ \~J
R~ /R2 R~o ,~R 1. H2, 10% Pd/C ~ / 2 ~10 1 --p~
~X. ~ 2. LiOH, THF . ~X~~ R5 ~ ,~R7) 3. (COC1)2. m(~ ~ ~R7) + Diastereomer R3 R4 Rg R8 n DMF, CH2CL2 /'~ ¦ Z R8 n 18 HN~ ~~, n-BuLi THF 26 ~Ph ¢COR 15 CHO ,D' R19 2. Dess-Martin (~ ~ --R ( ~R5 Oxidation m /~Z~R 7) n m /Y~ R7) ~COR 15 1. LAH, THF R1 /R2 Rlo 26 Oxidation [~ ~ , R5 3. Referto Scheme I m /Y\~ ~;8 n The chiral tricyclic derivatives of general structure 28 and 29 can be prepared in accordance with reaction Scheme VII. The previously described ~,~-unsaturated esters 18 (see reaction Scheme V) are reduced by catalytic hydrogenation over 10% palladium-on-DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

carbon in ethyl acetate to provide the intermediate saturated esters which are converted to the diastereomeric acyl oxazolidinones of general structure 2~ and 26 by coupling of the acid chloride derivative with (S)-4-benzyl-2-oxazolidinone. The mixture of amidediastereomers is separated by silica gel chromatography and each is separately reduced with 5 LAH at reduced temperatures in THF, followed by Dess-Martin oxidation in methylene chloride at ambient temperature to provide the diastereomerically pure tricyclic aldehyde, for example tricyclic aldehydes of general structure 27. In accordance with the processes employed in reaction Scheme I, the aldehydes are transformed into the tricyclic derivatives of general structure 28 and 29.
Scheme VIII: SYnthesis of Compounds of Structure (II):

Scheme Vlll.

DIBAL [~
21 ~ m /X\~ Z~R 7) R3 R4 Rg Diethyl (2-oxopropyl)-O phosphonate / R~50C~

R1s~ NaH/ R1s~

~R6 1. H2, Pd-C \ /~RR6 ~ ~ R7 ) 2. Trimethyl phos- ( ~\~ ,~ R7 ) m/Y\ ¦ R8 n phono~t~t~ NaH m /Y\ r ~;8 n R3 R4 Rg R3 R4 Rg The tricyclic derivatives of general structure 32 can be prepared in accordance with 15 reaction Scheme vm. The previously described saturated nitriles 21 (see Scheme VI) are reduced with DIBAL in methylene chloride at -78~C to provide aldehydes of general DOCK~ET NO. CA 02209134 1997-06-27 016-00 19A.WO

structure 30. The tricyclic aldehydes can be condensed with the sodium salt of diethyl (2-oxopropyl)-phosphonate in T~ at reduced temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide the a,~-unsaturated ketones 31. The enones 31 can be reduced by catalytic hydrogenation over 10% p~ m-on-carbon in ethyl acetate S to provide the interme~ te saturated ketones which are condensed with the sodium salt of trimethyl phosphonoacetate in THF at reduced temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide ~,~-unsaturated esters of general structure 32. The acids and salts derived from 32 are readily obtainable from the corresponding esters by the same processes as those employed in the plepal~ion process of Scheme I for tricycles of 10 general structure 6 and 7.
Scheme IX: Svnthesis of Compounds of Structure (m):

R1 /R2 ~ )n R1 /R2 ~ ' )n ~X ~ o (EtO)2P(O)CH2CN ~ ,~"CN

m~Y~J\R10 NaH/THF m /Y\/~\R1O
R3 R4 Rg R3 R4 Rg 1- H2, Pd-C
2. DIBAL
1. DIBAL /
3. 5, nBuLi DMPU, THF
/ 2. 5, nBuLi ~,/ DMPU, THF

R~ COF'.~s R3 R4 Rg 36 The tricyclic derivatives of general structures 3~ and 36 can be prepared in accord-ance with reaction Scheme IX. The tricyclic trienes 35 can be prepared from the correspond-15 ing tricyclic ketones 33 in a manner analogous to that described in the preparation process of DOCK~ETNO. CA 02209134 1997-06-27 016-0019A.WO

Scheme I for tricyclic derivatives of structures 6 and 7. The tricyclic dienes of general struc-ture 36 are prepared from the tricyclic ketones 33 in a manner analogous to that described in the preparation process of Scheme I and Scheme VI for tricyclic derivatives of general structure 22.
5 Scheme X: Synthesis of ComPounds of Structure (~1):

OH

R1 ~R2 ~ R6 H2N-OH-HCI ~R LAH
m/y\~\:~\z~ 7 ) Pyr/EtOH m( y ~\~ ~\~z~ 7 ) ~COR,5 ~COR15 ~R19 ( ~Z ~R ) ~ NaH, THF m 38 ~COR15 40 41 ~R19 DCC, DMAP, HOOC 41 CSA cat., CH2C12 ¢COR15 O ~ R19 m ( ~6 The tricyclic derivatives of general structures 40 and 42 can be prepared in accord-ance with reaction Scheme X. The previously described tricyclic ketones 1 (see preparation process for reaction Scheme I) are heated at reflux with hydroxylamine hydrochloride in DOCKJET NO. CA 02209134 1997-06-27 016-0019A.WO

pyridine and ethanol to provide oximes 37. A Beckman rearrangement is effected with LAH in ethanol at 80~C to afford the corresponding tricyclic amines 38, which are depro-tonated with NaH at 0~C in THF and alkylated at ambient temperature with ethyl (2E,4E)-6-bromo-3-methylhexa-2,4-dienoate to give aminodienes of general structure 40. Alterna-5 tively, the tricyclic amines 38 can be acylated by a DCC coupling in methylene chloridewith (2E,4E)-3-methyl-5-carboxypenta-2,4-dienoate to give amides of general structure 42. The acids and salts derived from the esters are readily obtainable by the same processes as those employed in the preparation process of Scheme I for tricycles of general structure 6 and 7.

[rest of page left purposely blank]

DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Scheme XI: Svnthesis of ComPounds of Structure (~:
R1 R2 R1o IH R\ /R2 R10 ~ AlCb l'X ~o DIBAL-H

R3 R4 Rg R3 R4 Rg 7 43 44 IrCOR15 H . IJ--~R~g Rl R2 R ¦ R1 R2 R
,y Refer to Scheme X ~ ~ h R3 R4 Rg R3 R4 Rg Refer to Scheme X

¢COR15 R1 /R2 R1 0 q5 R19 m /y S The tricyclic derivatives of general structure 46 and 47 can be prepared in accord-ance with reaction Scheme XI. The tricyclic amides 44 can be prepared from oxindole of general structure 43 and 2,5-dichloro-2,5-dialkylhexanes of general structure 17 by alumi-num trichloride catalyzed Friedel-Crafts alkylation/cyclization in dichloromethane at ambi-ent temperature. Amides of general structure 44 can be reduced with DIBAL in methylene DOCK~ETNO. CA 02209134 1997-06-27 016-0019A.WO

chloride at 25~C to provide the corresponding amines 45. The amine dienes 46 can be pre-pared from the amines 45 in a manner analogous to that described in the preparation pro-cess of Scheme X for tricyclic derivatives of general structure 40. The desired tricyclic amides 47 are prepared from the corresponding tricyclic amines of 45 in a manner analo-5 gous to that described in the preparation process of Scheme X ~or tricyclic derivatives ofgeneral structure 42. The acids and salts derived from 46 and 47 are readily obtainable from the corresponding esters by the same processes as those employed in the Scheme I for tricycles of structures 6 and 7.
Scheme XII: Svnthesis of Compounds of Structure (I~:

R1 ,R2 1"'~ ) n R1 R2 ~ ) n ~X~ ,~ o H2N-OH-HCI ~X~ ,~ ,OH

~ Pyr/EtOH ( ~R10 m(~ ~ "

49 50 C~R1 The tricyclic derivatives of general structure 50 can be prepared in accordance with 15 reaction Scheme XII. The tricyclic ketones 33 are transformed to amines of general structure 49 via Beckman type rearrangement of the intermediate oximes 48. Alkylation of the derived amines 49 with suitable alkyl halides of the type 38 provide the desired tricylcic derivatives of general structure 50. The acids and salts derived from 50 are readily obtain--- :=
DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

readily obtainable from the corresponding esters by the same processes as those employed in Scheme I for tricycles of structures 6 and 7.
- Scheme XIII: Svnthesis of ComPounds of Structure (III):

R1~R2 R10 R1~R2 R10 R2~q R7R8C=CR5C02H R2 ~ R5~C~2H
29~ Z m( ~ K R8 ~R~LR5 Refer to R ""~ f R5 100 ~~ (R2 ~l Z'\R 7 Scheme 1 R2~ ~8R7 An alternative means for making the intermediate tricyclic derivatives of general structure 54 is in accordance with reaction Scheme XIII. The reviously described tricyclic ketones 1 (see Example 1 ) can be prepared in an alternative fashion, starting from the tetra-hydronaphthylene 51. A Michael addition is effected by the addition of an acyrylic acid 10 (which can be trisubstituted) to the tetrahydronaphthylene 52 in toluene and heating the soution to 110 ~C for 8-16 hours. The tricyclic ketones 53 are formed by intramolecular acylation in polyphosphoric acid (PPA) at 100 ~C for 8-14 hours. The ketones are converted into tricyclic derivatives 54 by condensation with the phosphonate 5 by the same proceses as those employed in the process of Scheme I.

DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Scheme XIV: Svnthesis of Compounds of Structure (~

R26~ R~MgCI, THF ~ Refer to R2~R5 mR3~R4 ~ m( ~ m~ ~9/ 4Y' ~ Z ~R8R7 ~,COR, 5 1) LDA, THF Rl R10 ~ ~
-78 ~c R26~ Referto Scheme ~26 ~

R3 R4 R ( R28~Z R8R7 The tricyclic derivatives of general structure 59 can be prepared in accordance with reaction Scheme XIV. Tricyclic ketones are condensed with Grignard reagents in TE~ or diethyl ether at ~0 ~C, in the presence of a co-solvent such as DMPU. Michael addition, followed by intrarnolecular cyclization in the presence of PPA, as in Scheme XIII, allows for the preparation of intermediate ketones such as 57. The resulting ketone can be alkylated with a varitety of electrophiles, in particular alkyl halides not restricted to methyl iodide. The ketones are converted into tricyclic derivatives 59 by condensation with the phosphonate 5 by the same proceses as those employed in the processs of Scheme I.

DOCK~ET NO. CA 02209l34 l997-06-27 016-0019A.WO

Scheme XV: Svnthesis of ComPounds of Structure (V):

R26~ ~R5 CH3CO2Et R1 ~R2 _~
R27~ r R6 LDA. THF ~ R27" ~ ~ --r ~ R6 m( r. ,~ ~ ~Z~R7 -78 ~C m(~\Z~R8R7 CH20H ,~ CH20H

LAH R2 ~ CHzCI2, Zn-Cu ~R6 m ~l~ ~ m( R29 J ~, ~ Rg 62 63 ~ COR1s Dess-, ~ Referto~
R2s 4 R8 m( 65 The tricyclic derivatives of general structure 65 can be preapred in acccordance with reaction Scheme XV. The tricycli ketones 60 can be transformed into the esters of general structure 61 by low temperature lithio enolate chemistry or a Reformatsky reaction procedure. Reduction of the ester to the alcohol 62 which facilitates the Simmons-Smith reaction. The Simmons-Smith reaction gives the spiro-cyclic cyclopropyl compound of general strucuture 63 Oxidation of 63 followed by the same processes as those employed in Scheme I prepare the acids and salts of general structure 65.

DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

Scheme XVI: Svnthesis of ComPounds of Structure (~1):

R1 ~R2 R1 o R1 ~R2 R10 R27~ ~ ~ ~ R27~ r ~w~
m( ~ \Z~3R7 ( R2~\ZJ~R7 R3 R4 Rg R3 R4 Rg Refer R1sOC /Refer to Scheme X COR,s ~ ~/ to Scheme X J~
R19 ~ O

R1 ~R2 IR10 ~ R1 ~R2 R
R ~ r ~w~ R23 x,~,w~

( R2 ~'~ R7 ( R2~ R7 The tricyclic derivatives of general structure 68 or 69 can be prepared in accordance with reaction Scheme XVI. The tricyclic cyclic-carboxylic derivatives (esters or amides) can be reduced with lithium ~ mimlm hydride in THF to give the heterocycles of general structure 67. The acids and salts derived from 68 or 69 are readily obtained from the corresponding esters by the same processses ad tose employed in Scheme X.

DOCK~ET NO. CA 02209134 1997-06-27 Scheme XVII: Svnthesis of ComPounds of Structure (m):

.- O~N~ I) AICI3, CH2CI2 O~N~T~

R4~R28 ~ 2) HNO 3, H2S04 R28~No2 R3 Rg R3 4 R

I) NaH, THF ,~ Scheme XIII ~ ~R5 RII R28 NH2 ~ R28~<~ R7 2) Zn, CaCI 2 R3 R4 Rg R3 R4 Rg R24 I)N~H,7,THF N~ s ~s 2) DIBAL, THF ~0 C R2sJ~N R7 R28 R8 RefertoSchemel R3 R4 Rg R24 8 R3 R4 Rg R24 Refer to 75 Scheme I

~COR 15 COR 15 1~ ~
1~--R~g ¢ R19 R28-- ~' ~ ~1' The tricyclic derivatives of general structure 76 or 77 can be prepared in accordance with reaction Scheme XVII. The acrylic acid derivative 70 can be cyclized with AICl3 in dichloromethane or other nonpolar solvent to give the bicylic compound 71. If X=N then the amide can be alkylated to add the Rl group function using sodium hydride in THF and a alkyl halide electrophhile. The nitro group can be reduced to the amine using zinc and DOCK3ET NO. CA 02209134 1997-06-27 016-0019A.WO

calcium chloride mono-hydrate. Followin the building of the tricylic compound 73 as shown in Scheme XlII The ketone 73is converted to the nitrile as in Scheme I and reduction with DIBAL gives the aldehyde and amine 74. A intermidate of the amide reduction process is the enamine compound of general strucuture 75 which is stable and can be isoloted. The mixture 5 of products can be treated with the phosphonate reagent in Scheme I and following the procedures given there the acids and salts of general structure 76 or 77 can be isolated.

Scheme XVIII: Svnthesis of Compounds of Structure (m):

R2~ R9 W-R.~,I, etOH R ~ f' ~ P~8~' ~\ R7 reflux 3-5 h ~ ~8~' /~\ P~
m\ ~9/ J;,F~ ¦ R8 m\ ~9/ 4;, ¦ R8 The tricyclic derivatives of general structure 78 can be preapred in acccordance with reaction Scheme XVIII. The tricyclic derivatives of general structure 60 can be reacted with various nucleophiles, in particular, but not limited to amine, hydroxylamine or hyrazine, which following dehydration give compounds of the general structure 78.
It will be understood by those skilled in the art that certain modifications can be made to the above-described methods that remain within the scope of the present invention. For example, the compounds of the present invention may also be produced in the form of the corresponding amides or esters, or pharmaceutically acceptable salts.
The structural formulas for Compounds 101a and 101b through 144a and 144b ofthe present invention are given on the following pages.

DOCK~ETNO. CA 02209134 1997-06-27 016-0019A.WO

R150C3~ R15~C~ R15~C~
.~ p ~

101a: R15 = ethoxy 102a: R15 = ethoxy 103a: R1s = ethoxy 101b: R15 = OH 1-02b: R15 = OH 103b: R15 = OH

R 1 50C~ R1 50C3_ R1 5OC3L

~~0~

104a: R15 = ethoxy 105a: R15 = ethoxy 106a: R1s = ethoxy 104b: R15 = OH 105b: R15 = OH 106b: R1s = OH

Rl5OC~ R1sOC3_~ ~COR15 C,P ~

107a: R15 = ethoxy108a: R15 = ethoxy 109a: R15 = ethoxy 107b: R15 = OH108b: R15 = OH 109b: R15 = OH

~,~COR 15~CO R 15 R 1 s P \~ ~

110a: R15 = ethoxy 111a: R15 = ethoxy 112a: R15 = ethoxy 110b: R1s = OH 111b: R15 = OH 112b: R1s = OH
~COR1s ~oR15 R1s~C~

113a: R15 = ethoxy 114a: R1s = ethoxy 115a: R1s = ethoxy 113b: R15 = OH 114b: R1s = OH 115b: R15 = OH

DOCK~ETNO. CA 02209134 1997-06-27 016-0019A.WO

COR1s COR15 R150C~p '~ S S ' 116a: R15 = ethoxy117a: R15 = ethoxy . 118a: R15 = ethHoxy 116b: R15 = OH117b: R15 = OH 118b: R15 = ~

~COR1sR150(~ COR1s S ' ~ ~
119a: R15 = ethoxy120a: R15 = ethoxy 121a: R15 = eOthHoxy 119b: R15 = OH120b: R15 = OH 121b: R15 =
COR1s rCOR1s ~COR1s d~ ,~ J~

122a: R15 = ethoxy123a: R15 = ethoxy 124a: R15 ~ ethoxy 122b: R15 = OH123b: R15 = OH 1 4b: R15 -COR1s ~COR1s R1sOC~

S ~ S ~ S

125a: R15 = ethoxy126a: R15 = etho~y 1227b: RR1s - eOthHoxy 125b: R15 = OH126b: R15 = OH 1 : 15 -COR15R150C~ ~COR,5 1~ ~
SX ~~U~ = S~) 128ab- R1s ~ eOthHoxy 129b R15 - OH 1330b- RR1s ~ othHoxy DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

~~O ~,~COR,5 fOR1s 131a: R1s = ethoxy 132a: R15 = ethoxy 133a: R15 = ethoxy 131b: R1s = OH 132b: R15 = OH 133b: R15 = OH
~COR15 ~COR 15 ;~\o 134a: R1s = etho~y 135a: R1s = ethoxy 136a: R15 = ethoxy 134b: R15 = OH 135b: R15 = OH 136b: R1s = OH

~)~b~

137a: R15 = ethoxy 138a: R15 = ethoxy 139a: R15 = ethoxy 137b: R15 = OH 138b: R15 = OH 139b: R15 = OH
~COR 15 ~COR 15 ~COR 15 ~ ~ ~ .
140a: R15 = ethoxy 141a: R15 = 142a: R15 = ethoxy 140b: R15 = OH ethoxy 142b: R15 = OH
141b: R15 = OH
R150C3_ 143a: R15 = ethoxy 144a: R15 = ethoxy 143b: R15 = OH 144b: R15 = OH

DOCR~ETNO. CA 02209134 1997-06-27 016-0019A.WO

COOH HO2C~

~J~' S~ 3-JIt/ CO~H

145a: R15 = ethoxy 146a: Rl5 = ethoxy 147a: R15 = ethoxy 145b: R1s = OH COOH 146b: R15 = OH 147b: R15 = OH
~C02H ~C02H

5~3~ 5~N~ ~5~N~

148a: R 15 = ethoxy 149a: R15 = ethoxy 150a: R 15 = ethoxy 148b: R15 = OH 149b: R15 = OH 150b: R15 = OH
~CO2H ~02H ~02H

Q~N~ N.~IH ~

151a: R15 = ethoxy 152a: R15 = ethoxy 153a: R15 = ethoxy 151b: R15 = OH 152b: R15 = OH 153b: R15 = OH

~C02H

154a: R15= ethoxy 154b: R15 = OH

DOCKET NO. CA 02209134 1997-06-27 01 6-0019A.WO

~ In another aspect, the retinoid compounds of the present invention are combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in m~mm~ n, and 5 more preferably, in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, e.g., intravenous, oral, topical, suppository or parenteral.
In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring 10 agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, gr~n~ ting agents, lubricants, binders, t1i.~integrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present 1 5 invention.
For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives, may also be included. Furthermore, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed.
For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as Eucerin~M (Beiersdorf). F.~mples of suitable cream bases are NiveaTM Cream (Beiersdorf), cold cream (USP), Purpose CreamTM (Johnson & Johnson) hydrophilic ointment (USP), and .
LubridermTM (Warner-Lambert).
The pharm~ce~ltical compositions and compounds of the present invention will generally be aflmini~tered in the form .of a dosage unit (e.g., tablet, capsule etc.) at from about 1 ,ug/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 ~lg/kg to about 250 mg/kg, and most preferably from about 20 !lg/kg to about 100 mg/kg. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
The compounds of this invention also have utility when labeled and used in assays to determine the presence of RARs and R~s. They are particularly useful due to their ability to S selectively bind to members of the RAR and RXR subfamilies and can therefore be used to determine the presence of RAR and RXR isoforms in the presence of other retinoid receptors or related intracellular receptors.
Due to the selective specificity of the compounds of this invention for retinoidreceptors, these compounds can also be used to purify samples of RARs and RXRs in . 10 vitro. Such purification can be carried out by mixing samples cont~ining retinoid receptors with one of more of the compounds of the present invention, so that the compound ~ligand) binds to the receptor, and then separating out the bound ligand/
receptor combination by separation techniques which are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others.
The compounds of the present invention also include racemate, individual stereoisomers and mixtures thereof. These isomers are then isolated by standard resolution techniques, including fractional crystallization and reverse phase and chiral column chromatography .
The compounds and pharmaceutical compositions of the present invention can :' advantageously be used in the tre~tm~nt of the diseases and conditions described herein. In this regard, the compounds and compositions will prove particularly useful in the treatment of skin-related diseases and conditions, such as acne, psoriasis, and photo damage, cancerous and precancerous conditions, diseases of the eye, cardiovascular diseases, infl~mm~tory and neurodegenerative diseases, diseases associated with human papilloma virus, improper pituitary function, modulation of apoptosis, diseases of the immune system, wound healing and restoration of hair growth.
Furthermore, the compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified retinoid compounds.
For example, the compounds are extremely potent activators of RARs and RXRs, preferably displaying 50% maximal activation of one or more of the retinoid receptors at a DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

concentration of l~ss than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM, and most preferably at a concentration of less than 10 nM:. Also, the RAR and R~ selective compounds of the present invention p~ ell~ially activate one subfamily of retinoid receptors at a level at least 5 2 times greater, preferably at least 5 times greater, more preferably at least 10 times greater, and most preferably at least 100 times greater than the other subfamily of retinoid receptors In addition, the compounds of the present invention also are easier to synthe.~i7e, provide greater stability and bioavailability, and appear to be less teratogenic in comparison to all-frans retinoic acid and 9-cis retinoic acid, known RAR and R~ active compounds, 1 0 respectively.
The invention will be further illustrated by reference to the following non-limiting Examples.

15 lrest of page left purposely blank]

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

~ EXAMPLE 1 Preparation of compound 101a accordin~ to Scheme I
Ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2~I-anthracen-l-ylidene]he~a-2,4-dienoate (structure 6, where R1~ R2, R3, R4, and Rlg are methyl, R5, R6, R7, Rg, Rg, and R1o are hydrogen, R15 is ethoxy, X, Y and Z are carbon, m= n = 1) To a solution of 1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracene (2.0 g,8.3 mmol) [prepared by Friedel-Cra~s alkylation/annl]l~tion of 1,2,3,4-~ tetrahydronaphthalene with 2,5-dichloro-2,3-dimethylhexane in the presence of al~minl~m trichloride at 0~C in dich!oromethane] in CH2C12 (100 ml) and pyridine (15 ml) at 0~C was added CrO3 (8.26 g, 82.6 mmol) in several portions. The reaction mixture was stirred at 0~C for 30 min, then allowed to warm up to room temperature and stirred for 10 h. The reaction mixture was poured over an ice-acid rnixture (lN HCI, 100ml), extracted with Et2O (200 ml), dried (MgSO4), concentrated, and purified by column chromatography (25% ether in hexane) to give 3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-one (740 mg, 35%): 1HNMR(400 MHz, CDCl3) o 8.01(s, lH, ArH), 7.17(s, lH, ArH), 2.90(t, J=6.5 Hz, 2H, CH2, benzylic), 2.60(t, J=6.3 Hz, 2H, CH2), 2.10(m, 2H, CH2), 1.68(s, 4H, 2CH2), 1.30~s, 6H, 2CH3), 1.29(s, 6H, 2CH3).
To a solution of diethyl cyanomethylphosphonate (1.8 g, 10.4 mmol) in THF (4 ml)and DM:PU (4 ml) at 0~C was added NaH (375 mg, 65% in oil, 10.4 mmol) in one portion.
The resulting solution was warmed to room temperature for 30 min. To this solution was added 3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-l-one (1.08 g, 4.2 mmol) in THF (2 ml). The mixture was then refluxed at 80~C for 3 hr, cooled, quenched with saturated NH4Cl (20 ml), extracted with Et2O (100 ml), dried (MgSO4), concentrated, and purified by column chromatography (10% ether in hexane) to afford cis-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethyl-2H-anthracen-1-ylidene)ethanitrile (100 mg, 10%) and ~rans-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethyl-2H-anthracen-1-ylidene)ethanitrile (660 mg, 66%). The cis-nitrile (structure 3) had lH NMR(400 MHz, CDC13) ~ 8.31(s, lH, ArH), 7.09(s, lH, ArH), 5. l9(s, lH, olefinic), 2.80(t, J=6.5 Hz, 2H, CH2, benzylic), 2.55(t, J=6.3 Hz, 2H, CH2), 1.90(m, 2H, CH2), 1.64(s, 4H, 2CH2), DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

1.26(s, 6H, 2CH3), 1.25(s, 6H, 2CH3). The trans-nitrile (structure 4) had lH NMR(400 MHz, CDC13) ~ 7.46(s, lH, ArH), 7.09(s, lH, ArH), 5.68(s, lH, CH, olefinic), 2.80(m, ,! 4H, 2CH2), l.90(m, 2H, CH2)~ 1.65(s, 4H, 2cH2)~ 1.26(s, 6H, 2CH3), 1.25(s, 6H, 2CH3) To a solution ofthe above Z-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-l-ylidene)ethanitrile (56 mg, 0.2 mmol) in CH2cl2 (2 ml) at -78~C was added DIBAL (0.4 ml, lM in CH2C12~ 0.4 mmol). The mixture was stirred at that temperature for 10 min, then quenched with saturated potassium sodium tartrate (10 ml) at -78~C, warmed to room temperature, extracted with EtOAc (50 ml), dried (MgS04), and concentrated to give essentially pure aldehyde, which was employed for the next reaction without further purification.
A solution of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (86 mg, 0.33 mmol) in THF (1 ml) and DMPU (1 ml) at 0~C was treated with nBuLi (O.13 ml, 2.5 M in hexane, 0.33 mM), then warmed to room temperature for 30 min. The solution was cooled to -78~C, and the above aldehyde (32 mg, O.11 mmol) in THF (1 ml) was slowly added. Subsequently, the reaction mixture was allowed to warm to room temperature for 30 min, quenched with a saturated solution of NH4Cl (5 ml), extracted with Et20 (50 ml), dried (MgS04), concentrated, and purified by column chromatography (10% ether in hexane) to give the title ester (lOla) (39 mg, 85%)~ 0.48(10 % ether in hexane); lH
NMR(400 MHz, CDC13) o 7.33(s, lH, ArH), 7. l9(dd, J=15.2, 11.2 Hz, lH, olefinic), 7.07(s, lH, ArH), 6.32(d, J=15.2 Hz, lH, olefinic), 6.14(d, J=11.2 Hz, lH, olefinic), 4.15(q, 2H, OCH2), 2.79(t, J=6.5 Hz, 2H, CH2), 2.50(t, J=5.8 Hz, 2H, CH2), 2.28(s, 3H, CH3), l.91(m, 2H, CH2), 1.68(s, 4X 2CH2), 1.29(s, 6H, 2CH3), 1.27(s, 6H, 2CH3), 1.24(t, J=6.8 Hz, 3H, CH3).

DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

EX~MPLE 2 Preparation of compound 101b according to Scheme I
(2E,4E)-3-Methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2~I-anthracen-l-ylidene]hexa-2,4-dienoic acid (structure 6, where Rl, R2, R3, R4, and Rlg are methyl, R5, R6, R7, Rg, Rg, and Rlo are hydrogen, Rls is hydroxy, X, Y, and Z are carbon, m =
1, and n = 1) To a solution of ester 101a (39 mg, 0.1 mmol) in MeOH (1 ml) and H2O (1 ml) was added KOH (100 mg, 2.5 mmol) at 25~C. The reaction mixture was heated at 80~C
for 3 hr, cooled, acidified (1.1 ml, 2.4 N HCI), extracted with Et2O (40 ml), dried (MgSO4), concentrated,-and purified using column chromatography (50% ether in hexane) to obtain the title compound 101b (35 mg, 95%): Rf~ 0.32(50 % ether in hexane); mp 225 - 227~C; lH NMR(400 MHz, CDC13) ~ 7.32(s, lH, ArH), 7.24(dd, J=15.2, 11.2 Hz, lH, olefinic), 7.07(s, lH, ArH), 6.34(d, J=15.2 Hz, lH, olefinic), 6.16(d, J=11.2 Hz, 1X
olefinic), 5.80(s, lH, olefinic), 2.79(t, J=6.4 Hz, 2H, CH2, benzylic), 2.51(t, J=5.8 Hz, 2H, CH2), 2.34(s, 3H, CH3), 1.92(m, 2H, CH2), 1.68(s, 4H, 2CH2), 1.29(s, 6H, 2CH3), 1.27(s, 6H, 2CH3).

Preparation of compound 102a according to Scheme I
Ethyl (21~,4E)-3-methyl-6-[(Z)-2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-cyclopenta[b]napthalen-l-ylidene]hexa-2,4-dienoate (structure 6, where Rl, R2, R3, R4, and Rlg are methyl, Rs, R6, R7, R8, Rg, and R1o are hydrogen, R15 is ethoxy, X, Y, and Z are carbon, m = 1, and n = 0).
The title compound was prepared in a manner similar to that of compound 101a except that 2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]naphthalen- 1 -one [US
patent 2,815,382 (1957)] was used as the starting ketone (structure 1) in Example 1.
Compound 102a had Rf= 0.56(10 % ether in hexane); lH NMR(400 MHz, CDC13) 7.68(s, lH, ArH), 7.45(dd, J=15.0, 11.6 Hz, lH, olefinic), 7.24(s, lH, ArH), 6.25( d, J=15.0 Hz, lH, olefinic), 6.22(d, J=11.6 Hz, lH, olefinic), 5.75(s, lH, olefinic), 4.15(q, DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

2H, OCH2), 2.88(bm, 2H, CH27 benzylic), 2.79(bm, 2H, CH27 allylic), 2.48(s, 3H, CH3), 1.68(s, 4H, 2CH2), 1.31(s, 26H, CH3), 1.29(m, 9H, 3CH3).

5 Preparation of compound 102b accordin~ to Scheme I
(2E,4E)-3-Methyl-6-[(Z)-2,3-5,6,7,8-hexahydro-5,5,8,8,-tetramethyl-cyclopenta[b]naphthalen-l-ylidenelhexa-2,4-dienoic acid (structure 6, where Rl, R2, R3, R4, and Rlg are methyl, R5, R6, R7, R8, Rg, and R1o are hydrogen, Rls is hydroxy, X, Y, and Z are carbon, m = 1, and n = 0).
The title compound was prepared by hydrolysis of compound 102a employing the standard hydrolysis conditions (KOH, MeOEI/H20) used in Example 2. Compound 102b had RfO.45 (50% ether in hexane); mp 240 - 241~C; lH NMR(400 MHz, CDCl3) o 7.67(s, lX ArH), 7.53(dd, J=15.0, 11.6 Hz, lH, olefinic), 7.24(s, lH, ArH), 6.29(d, J=15.0 Hz, lH, olefinic), 6.26(d, J=11.6 Hz, lH, olefinic), 5.80(s, lH, olefinic), 2.91(bm, 2H, CH2, benzylic), 2.81(bm, 2H, CH2, allylic), 2.40(s, 3H, CH3), 1.69(s, 4H, 2CH2), 1.31(s, 6X 2CH3), 1.27(s, 6H, 2CH3).

Preparation of compound 103a accordin~ to Scheme I
Ethyl (2E,4E)-3-methyl-6-[(Z)-1,2,3,6,7,8-he~ahydro-1,1,3,3-tetramethyl-cycopenta~b]naphthalen-5-ylidene]hexa-2,4-dienoate (structure 6, where Rl, R2, R3, R4 and R1g are methyl, Rs, R6, R7, Rg, Rg, and Rlo are hydrogen, R1s is ethoxy, X, Y, and Z are carbon, m=0 and n=l).
The title compound was prepared from 1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethyl-cyclopenta[b]naphthalen-5-one. The preparation of this naphthalen-5-one was achieved as follows. 3,3-Dimethylcrotyl chloride was treated with 1,2,3,4-tetrahydronaphthalene in the presence of ~Illmimlm trichloride to give the corresponding 1,2,3,5,6,7,8-heptahdyro-1,1-dimethyl-3-oxo-cyclopenta[b]naphthalene, which was then geminally dimethylated with dimethyl zinc in the presence of titanium tetrachloride to afford 1,2,3,5,6,7,8-heptahdyro-1,1,3,3-tetramethyl-cyclopenta[b]naphthalene. The naphthalene derivative was then oxidized using CrO3 in acetic acid in a manner similar to that described in Example 1. The DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

title compound 103a had RfO.85 (10% ether in hexane); lH NMR (400 MHz, CDC13) o 7.20 (dd, J=15.2, 11.2Hz, lH, olefinic), 7.15 (s, lH, ArH), 6.91 (s, lH, ArH), 6.32 (d, J=15.2 Hz, lX olefinic), 6.19 (s, J=11.2 Hz, lH, olefinic), 5.77 (s, lH, olefinic), 4.16 (q, 2X OCH2), 2.83 (t, J=6.5 Hz, 2H, CH2 benzylic), 2.53 (t, J=6.1 Hz, 2H, CH2 allylic), 2.28 (s, 3H, CH3), 1.91 (m, 2H, CH2~ methylene), 1.90 (s, 3H, CH2~ methylene), 1.43 (s, 6H, 2CH3), 1.32 (s, 6H, 2CH3), 1.27 (t, J=6.7 Hz, 3H, CH3).

Preparation of compound 103b accordin~ to Scheme I
(2E,4E)-3-Methyl-6-1(Z)-1,2,3,6,7,8-he~ahydro-1,1,3,3-tetra-cyclopenta[blnaphthalen-5-ylidene~he~a-2,4-dienoic acid (structure 6, where R1, R2, R3, R4, and R1g are methyl, R5, R6, R7, R8, Rg, and Rlo are hydrogen, Rls is hydroxy, X, Y, and Z are carbon, m=O, and n=l).
The title compound was prepared by hydrolysis of ester 103a using the standard hydrolysis conditions employed in Example 2. Compound 103b had RfO.30 (40% ether in hexane); mp 192-194~C; 1H NMR (400 MHz, CDCl3) o 7.26 (dd, J=15.2, 11.2 Hz, lH, olefinic), 7.14 (s, lH, ArH), 6.92 (s, lH, ArH), 6.35 (d, J=15.2 Hz, lH, olefinic), 6.19 (d, J=11.2 Hz, lH, olefinic), 5.80(s, lH, olefinic), 2.83 (t, J=6.5 Hz, 2X CH2, benzylic), 2.55 (t, J=6.1 Hz, 2H, CH2, allylic), 2.30 (s, 3EI, CH3), 1.95 (s, 2H, CH2, methylene), 1.93 (m, 2H, CH2, methylene), 1.32 (s, 6H, 2CH3), 1.31 (s, 6H, 2CH3).

Preparation of compound 104 b accordin~ to Scheme I
(2E,4E)-3-Methyl-6-(2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-hexamethylbenzo[bl-chromen-4-ylidene)-he~a-2,4-dienoic acid ( structure 6, where R1, R~ R3, R4, R7, R8, and Rlg are methyl, Rs, R6, Rg, Rlo are hydrogen, R1s = OH, X and Y are carbon, Z is oxygen, m =n= 1).
The title compound was synthesized in a manner similar to that of compound 101b except 3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethylnaphtho(2,3-b)-1,2-pyran-4-one (structure 1) was employed as the starting ketone. The synthesis ofthe pyran-4-one is DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

detailed here. ~ minllm trichloride (25 g, 0.18 M) was added in portions to a solution of phenol (49.5 g, 0.52 M) and 2,5-dichloro-2,5-dimethylhexane (101.0 g, 0.55 M) indichloromethane (700 ml). The reaction mixture was allowed to stir at 25-40~C for 2 h, then the dark red mixture was poured onto ice. Aqueous work up (EtOAc extraction) gave 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol as a white solid, which was recrystallized from hexane to give colorless needles (84.8 g, 0.42 moles, 80%): lH NMR
(400 MHz, CDC13) o 7.17 (d, lH), 6.78 (d, lH), 6.62 (dd, lH), 4.55 (s, lH), 1.65 (s, 4H), 1.25 (s, 12H). The hydroxynaphthalene (19. lg, 93.6 mmol) was treated dropwise with acetyl chloride (7.7 g, 98.2 mmol) in 1,2-dichloroethane (250ml) at 0~C. Af~er completion ofthe addition, ~lllmin~m chloride (10 g, 75.2 mmol) was added in portions over 5 min. The mixture was refluxed for 10 h, then stirred at 25~C for 8 h. GLC analysis indicated the desired keto-phenol was present in 98.6% purity. The reaction mixture was poured onto ice and aqueous work up (EtOAc extract) gave a brown-black solid, which was dissolved in hot methanol, filtered, and concentrated to give a brown viscous semi-solid. Flash chromatography (15 % EtOAc/hexane) gave 1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)ethanone as a light yellow solid.
Recrystallization from hexane afforded white crystals (15.2 g, 61.8 mmol, 66%): lH NMR
(400 MHz, CDC13) ~ 7.63 (s, lH,), 6.9 (s, lH), 2.61 (s, 3H), 1.67 (s, 4H), 1.29 (s, 6H), 1.27 (s, 6H).
A solution ofthe above hydroxyacetophenone (1.86 g, 7.5 mmol), pyrrolidine (590 mg, 7.5 mmol), acetone (850 mg, 14.6 mmol), and a catalytic amount of p-TsOH in benzene (650 rnl) was heated at reflux for 48 hours. The mixture was cooled to 25~C and diluted with 1 N HCI (35 ml). Aqueous work up (Et2O extraction) gave a yellowish brown solid. Recryst~ tion from hexane afforded 2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-hexamethylbenzo[g]chromen-4-one (structure 1) as fine white crystals (560 mg, 1.95 mmol, 26%): lH NMR (400 MHz, CDC13) o 7.3 (s, lH), 6.85 (s, lH), 2.68 (s, 2H), 1.68 (s, 4H), 1.45 (s, 6H), 1.26 (s, 12H).
The above tricyclic ketone (556 mg, 1.95 mmol) was olefinated by means of the procedure described in Example 1 to give a crude mixture of cis and trans unsaturated nitriles. Flash chromatography (8% EtOAc/hexane) afforded (E)[2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-hexamethylnaphtho-(2,3-b)-1,2 pyran-4-ylidene]ethanitrile as a light yellow DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

solid (210 mg, 0.68 mmol): lH NMR (400 MHz, CDC13) d7.35 (s, lH), 6.8 (s, lH), 5.7 (s, lH), 2.82 (s, 2H,), 1.65 (s, 4H), 1.40 (s, 6H), 1.26 (d, 12H); and the (Z)-[2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-hexamethylnaphtho (2,3-b)-1,2 pyran-4-ylidene]ethanitrile as a yellow solid (120 mg, 0.38 mmol): lH N~ (400 M:Hz, CDC13) ~ 8.30(s, lH), 6.3(s, lH), 5.08 (s, lH), 2.52 (s; 2H), 1.67 (s, 4H), 1.40 (s, 6H), 1.30 (s, 6H), 1.27 (s, 6H ), 1.25 (s, 6H ).
The cis-nitrile (120 mg, 0.38 mmol) in TE~ mL was reduced to the corresponding aldehyde (by treatment with DlBAL at -78~ under nitrogen). GLC analysis was used to monitor the reaction due to the tendency of the cis product to isomerize in the presence of .10 DIBAL. The reaction was stopped when the appearance ofthe b~ans product wasdetected by GLC. Aqueous work up (EtOAc extraction) gave an orange oily solid (95 mg). Flash chromatography (8% EtOAc/hexane) afforded [(E)-2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-hexamethylnaphtho (2,3-b)-1,2 pyran-4-ylidene]acetaldehyde as a light yellow solid (20 mg, 0.06 mmol, 16% yield): lH NMR (400 MHz, CDC13) ~ 10.1 (d, lH), 7.26 (s, lH), 6.8 (s, lH), 5.9 (d, lH), 2.58 (s, 2H), 1.70 (s, 4H), 1.4 (s, 6H), 1.26 (s, 6H), 1.24 (s, 6H).
The above aldehyde (19mg, 0.06 mmol) was converted to the title triene ester using the procedure similar to that described in Example 1. A total of 2.4 eq of phosphonate and base (nBuLi) was used. Aqueous work up, followed by flash chromatography (20%
EtOAc/hexane) afforded a mixture of ethyl (2E,4E)- and (2Z,4E)-6-(2,3,6,7,8,9-hexahydro-benzo[g]-chromen-4-ylidene)-3-methylhexa-2,4-dienoate as a yellow oil ~23.5mg, 0.055 mmol, 94% yield). lH NMR indicated a 9:1 ratio of isomers favoring the trans product: lH NMR (400 MHz, CDC13) ~ 7.40 (s, lH), 7.35 (dd, lH), 6.77 (m, lH), 6.40 (d, lH), 6.05 (d, lH), 5.8 (s, lH), 4.20 (m, 2H), 2.43 (s, 2H), 2.35 (s, 3H), 1.67 (s, 4H), 1.33 (s, 6H), 1.31 (t, 3H), 1.30 (s, 6H), 1.25 (s, 6H). The isomers could not be separated by chromatography and were used as a mixture in subsequent reactions.
The above mixture of esters (23mg, 0.054 mmol) was hydrolyzed to the corresponding acids according to the procedure described in Example 2. Removal of solvent gave the title compound as a yellow solid (1 9mg, 0.048 mmol, 90%). A 2.5mg sample of the crude material was purified by HPLC (80:20=MeOH: 10 mM ammonium DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

acetate) to give the title acid 104b as a bright yellow solid (1.Smg): TLC, Ri~0 31(20%
acetone/hexane) lH NMR (400 MHz, CDC13) o 7.40 (dd, lH), 7.35 (s, lH), 6.77 (s, lH), 6.40 (d, lH), 6.08 (d, lH), 5.85 (br s, lH), 2.45 (s, 2H), 2.35 (s, 3H), 1.70(s, 4H), 1.36 (s, 6H), 1.30 (s, 6H), 1.25 (s, 6H).

Preparation of compound 105a accordin~ to Scheme I
Ethyl (2E,4E)-3-methyl-6-[(:Z;)-3,4,5,6,7,8-he~ahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]he~a-2,4-dienoate (structure 6, where R1, R2, R3, R4, and R1g ~ 10 are methyl; Rs, R6, R7, Rg, and R1o are hydrogen; Rg is nitro; R1s is ethoxy; X, Y, Z are carbon, m = n = 1) The title compound was prepared according to Example 1 except that 10-nitro-1,2,3,4,5,6,7,8 octahydro-5,5,8,8-tetramethylanthracene was used as the starting rnaterial.
The synthesis of this intermediate is described below.
1,2,3,4,5,6,7,8-Octahydro-5,5,8,8-tetramethylanthracene (1.1 g, 4.5 mmol) was suspended in acetic acid (4 mL) and concentrated sulfuric acid (0.5 mL). The mixture was cooled to 10~C, and nitric acid (3 mL) was added dropwise so that the internal temperature remained below 20~C. The mixture was allowed to warm to room temperature and stirred for 1 h. The dark red mixture was diluted with ice/water (10 mL) and extracted with EtOAc (3 x 20 mL). The EtOAc layer was washed with water, saturated aqueous NaHCO3, water, and brine. The solution was dried (Na2S04), filtered, and concentrated to give a brown oil. The crude product was crystallized with CH2Cl2/ether/hexanes to give 10-nitro-1,2,3,4,5"6,7,8-octahydro-5,5,8,8-tetramethylanthracene 1.2 g (94%) as a yellow solid: mp 129.3-130.7~C; IR (thin film) 2930 s, :2864 s, 1526 s, 1470 m, 1435 m, 1369 s, 1269 w, 1128 w, 918 w, 754 m cm~l; 1HNMR(400 MHz, CDCl3) o 7.14 (s, lH, aromatic), 2.72 (br s, 2H, CH2), 2.50 (br s, 2H, CH2), 1.75 (m, 6H, 3CH2), 1.65 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.29 (s, 6H, 2CH3).
10-Nitro-1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-one (structure1, where R1, R2, R3, R4 are methyl; Rs, R6, R7, Rg, and R1o are hydrogen; Rg is nitro;
X, Y, Z are carbon, m = n = 1) was prepared according to Example 1 except chromium DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

trioxide in acetic acid was used as the oxidant to give 148 mg (83% based on recovered starting material) of the ketone as a yellow solid: mp 134.0-136.5~C; IR (thin film) 2964 s, 2931 s, 1693 s, 1597 s, 1531 s, 1468 s, 1413 m, 1389 s, 1372 s, 1337 m, 1263 s, 1249 s, 1232 m, 1178 m, 1053 m, 912 m, 750 m cm~l; lH NMB (400 MHz, CDC13) ~ 8.17 (s lH,aromatic), 2.71 (t, J=6.2 Hz, 2H, CH2)~ 2.63 (t, J=6.6 Hz, 2H, CH2)~ 2.12 (m, 2H, CH2);
1.74 (m, 2H, CH2), 1.70 (m, 2H, CH2), 1.35 (s, 6H, 2CH3), 1 33 (s, 6H, 2CH3); MS (CI) m/e 302 (MH+, 100), 289 (30), 272 (9).
Using the procedure described in Example 1, the above ketone was transformed into the title compound 105a which was obtained as a yellow oil: lH NMR (400 MHz, CDC13) ~ 7.42 (s, lH, aromatic), 6.98 (dd, J=15.2, 11.0 Hz, lH, olefonic), 6 34 (d, J=15 2 Hz, lH, olefonic), 6.21 (d, J=l 1 0 Hz, lH, olefonic), 5.77 (s, lH, olefonic), 4.14 (q, J=7.0 Hz, 2H, -OCH2), 2.56 (t, J=6.6 Hz, 2H, CH2)~ 2.44 (br t, J=6.2 Hz, 2H, CH2), 2.23 (d, J=0 8 Hz, 3H, CH3 allylic), 1.88 (m, 2H, CH2)~ 1.71 (m, 2H, CH2)~ 1.66 (m, 2H, CH2), 1.30 (s, 6H, 2CH3), 1 28 (s, 6H, 2CH3), 1.28 (t, J=7.0 Hz, 3H, CH3 ethyl).

Preparation of compound 105b according to Scheme I
(2E,4E)-3-Methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2E-anthracen-1-ylidene]hexa-2,4-dienoic acid (structure 6, where R1, R2, R3, R4, and R1g are methyl; Rs, R6, R7, Rg, and R1o are hydrogen; Rg is nitro; R15 is hydroxy, X, Y, Z
are carbon, m = n= 1).
Compound 105a was hydrolyzed using the procedure of Example 2, to give the title compound 105b 3.3 mg (31%) as a yellow film: lH NMR (400 MHz, CDC13) o 7.45 (s, lH, aromatic), 7.08 (dd, J=15.2, 11.2 Hz, lH, olefonic), 6.42 (d, J=15.2 Hz, lH, olefonic), 6.25 (d, J=11.2 Hz, lH, olefonic), 5.84 (s, lH, olefonic), 2.60 (t, J=6.6 Hz, 2H, CH2), 2.49 (br t, J=6.3 Hz, 2H, CH2), 2.29 (d, J=0.8 Hz, 3H, CH3 allylic), 1.93 (m, 2H, CH2), 1.75 (m, 2X CH2), 1.69 (m, 2H, CH2), 1.34 (s, 6H, 2CH3), 1.33 (s, 6H, 2CH3).

Preparation of compound 106a accordin~ to Scheme II

DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

Ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-he~ahydro-4,5"5,5,8,8-hexamethyl-2H-anthracen-1-ylidene]he~a-2,4-dienoate (structure 6, where Rl, R2, R3, R4, and R1g are methyl, R5, R6, R7, Rg, Rg, Rlo are H, R15 is ethoxy, X and Y are carbon; Z is C(CH3)2;
m= n=l).
A 100 mL round-bottom flask was flame dried under a nitrogen atmosphere, charged with dichloromethane (20.0 mL) and cooled to -40~C. A solution of titanium tetrachloride in toluene (2.0 M, 11.7 mL; 23.4 rnM) was added, followed by a solution of dimethylzinc in toluene (10 M, 11.7 mL, 11.7 mM). The mixture was stirred at -40~C for 30 min and a solution of 3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-l-one ~ 10 (1.0 g, 3.9 mmol, from Example 1) in dichloromethane (20 mL) was slowly added. The reaction mixture was warmed to room temperature and stirred for 36 h. The rnixture was poured onto a solution of methanol and dry ice, followed by saturated ammonium chloride.
The solution mixture was extracted with CH2C12, washed with water (3 x 20 mL), and brine (3 x 20 rnL). The solvent was evaporated and the crude residue was purified by flash chromatography using hexanes as an eluent to give 937 mg of 1,1,5,5,8,8-hexamethyl-1,2,3,4,5,6,7,8-octahydroanthracene, 89% yield: lH NMR (400 MHz, CDC13) o 7.23 (1 H,Ar),6.93(1H,Ar),2.70(t,J=8.0Hz,2H), 1.78(m,2H), 1.65(s,4H), 1.63(m,2H), 1.27(s,3H), 1.26(s,6H), 1.25(s,3H).
A solution of chromium trioxide (13.55 mL of a 10% CrO3/AcOH solution) was slowly added to a solution of finely ground 1,1,5,5,8,8-hexamethyl-1,2,3,4,5,6,7,8-octahydroanthracene (861 mg, 3.18 mmol) in AcOH (12 mL) at 25~C. The mixture wasstirred for 30 min. Ice water (100 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The organic extracts were combined and twice treated with Et3N (10 mL), and washed and with sat. NaHCO3 (20 mL), water (2 x 20 mL) and brine (2 x 20 mL). The solvent was evaporated and the crude residue was purified by silica gelchromatography (hexanes:EtOAc 9: 1) to give 831 mg of pure 3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracen-1-one (structure 1 where Rl, R2, R3, and R4 are methyl, Rs, R6, R7, Rg, Rg, and Rlo are hydrogen, X and Y are carbon, Z is C(CH3)2 and m - n = 1): lH NMR (400 MHz, CDC13) ~ 7.97 (s, lH, Ar), 7.31 (s, lH, Ar), 2.68 (t, DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

J=8.0 Hz, 2H), 1.98 (t, J=6.0 Hz, 2H), 1.68 (s, 4H), 1.37 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H). The above ketone was transformed to the title compound as outlined in Scheme II.
A 50 mL round-bottom flask was flame-dried and charged with anhydrous THF (10 mL) and ethyl magnesium bromide (2.65 mL of 1 M solution in THF, 2.65 mM) and the 5 structure was cooled to 0~C. Under a nitrogen atmosphere, a solution of ethyl ethynyl ether (0.375 mL of a 50% solution in hexanes, Aldrich Inc., 2.63 mM) was slowly added.
The crude mixture was warmed to room temperature and stirred for 20 min. A solution of 4,4,5,5,8,8-hexamethyl-1,2,3,4,5,6,7,8-octahydroanthracen-1-one (0.50 g, 1.76 mmol) in THF (10 mL) was slowly added and stirring was continued for 2 h. The reaction mixture 10 was quenched with a sat. solution of ammonium chloride and extracted with diethyl ether.
The organic layer was dried over MgS04, and the solvent evaporated. The crude residue was dissolved in ethanol (20 mL) and CO2 (dry ice) was bubbled through the solution for 3 h. After stirring for 12 h at 25~C, the solvent was evaporated and the residue was purified by silica gel chromatography to give 455 mg (73% yield) of a mixture of (Z) and (E) esters in a 3.5: 1 ratio. The mixture of esters (455 mg, 1.28 mmol) was dissolved in anhydrous dichloromethane (5.0 mL) and cooled to -78~C. DI13AL in dichloromethane (3.2 mL of 1.0 M solution, 3.2 mM) was added and the mixture stirred for 15 min. The reaction was quenched at -78~C using a saturated solution of Rochelle salt and extracted withdichloromethane. The organic layer was dried over MgSO4, then evaporated to give a 20 white residue which was purified by chromatography to afford the corresponding cis allylic alcohol (211 mg) and trans allylic alcohol (37 mg). The cis-alcohol 2-[(Z)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracene-1-ylidine] ethanol: lH NMR (400 MHz, CDCl3) o 7.25 (s, lH, Ar), 7.03 (s, lH, Ar), 5.57 (t, J=4.5 Hz, lH), 4.43 (t, J=4.5 Hz, 2H), 2.46 (m, 2H), 1.75 (m, 2H), 1.67 (s, 4H), 1.28 (s, 18H). The trans-alcohol 2-[(E)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8 -hexamethyl-2H-anthracene- 1 -ylidine] ethanol; 1 H N~
(400MHz,CDCl3)~7.56(s, lH,Ar),7.02(s, lH,Ar),6.15(t,J=4.5Hz, lH),4.39(t, J=4.5 Hz, 2H), 2.46 (m, 2H), 1.75 (m, 2H), 1.68 (s, 4H), 1.27 (s, 18H).
To a solution of 2-[(Z)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracene-1-ylidine] ethanol (100 mg, 0.32 mmol) in dichloromethane (2.0 mL) was added a total of 200 mg of MnO2 in 4 portions. The mixture was stirred for 1 h, then filtered through a pad of celite and thoroughly rinsed with dichloromethane (total of 20 DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

mL). The solvent was evaporated to give 93 mg of the virtually pure corresponding aldehyde (98% yield) which was used directly in the next step. A flame-dried 25 mL
round-bottom flask was charged into diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (142 mg, 0.53 mmol) and anhydrous THF (15.0 mL) and the solution was cooled to 0~C. Anhydrous DMPU (0.25 mL) and nBuLi in hexanes (0.34 mL of 1.5 M
solution, 0.51 mM) were added. The mixture was stirred at 0~C for 20 min, then cooled to -78~C. A solution of the above aldehyde in THF (3.0 mL) was added dropwise. After stirring at -78~C for 10 min, the mixture was allowed to warm to room temperature. After 30 min, the reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated. The residue was purified by chromatography to give the title ester 106a (108 mg, 86% yield): lH NMR (400 MHz, CDCl3) ~ 7.25 (m, 3H, 2ArH and l vinylic H), 6.38 (d, J=16 Hz, lH), 6.27 (d, J=12 Hz, lH), 5.80 (s, lH~, 4.1 (q, J=4.5 Hz, 2H,O-CH2-),2.55(t,J=4.5Hz,2H),2.32(s,3H,CH3), 1.78(t,J=4.0Hz,2H), 1.69(s, 4H), 1.30 (s, 18H), 1.28 (t, J=4.0 Hz, 3H). 1H NMR data indicated the presence of a geometric isomer at the 2,3 double bond in a ratio of frans:cis 5: 1.

Preparation of compound 106b according to Scheme II
(2E,4E)-3-Methyl-6-l(Z)-1,2,3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2EI-anthracen-1-ylidene]hexa-2,4-dienoic acid (structure 6 where R1, R2, R3, R4, and R1g are methyl; R5, R6, R7, R8, Rg, and R1 o are H; R15 is hydroxy; X and Y are carbon; Z is C(CH3)2; m= n= 1) To a solution ofthe above compound 106a (108 mg, 0.23 mmol) in ethanol (3.0 mL) was added NaOH (100 mg) and water (3.0 mL). The mixture was heated at 70~C for 4 h, then cooled to room temperature, acidified using 1 N HCI, and extracted with EtOAc (20 mL). The organic layer was washed with water (2 x 10 mL), brine (2 x 10 mL) and dried over MgSO4. The solvent was evaporated and the residue was recrystallized from acetone-water three times to give the geometrically pure title acid 106b in 56%: lH NMR
(400 MHz, CDC13) ~ 7.25 (m, 3 H, 2ArH and 1 vinylic H), 6.38 (d, J=16 Hz, lH), 6.27 (d, - DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

J=12 Hz, lH), 5.80 (s, lH), 2.55 (t, J=4.5 Hz, 2), 2.32 (s, 3H, CH3), 1.78 (t, J=4.0 Hz, 2H~, 1.69 (s, 4H), 1.3 (s, 18H).

$ Preparation of compound 107b according to Scheme II
(2E,4E)-3-Methyl-6-[(Z)-2,3,5,6,7,8-hexahydro-3,S,5,8,8-pentamethyl-cyclopenta~b]naphthalen-1-ylidene]he~a-2,4-dienoic acid (structure 6, where R1, R2, R3, R4 and Rlg are methyl; R5, R6, Rg and Rlo are hydrogen; R15 is hydroxy; X and Y
are carbon; Z is CHCH3; m = 1 and n = 0) The title acid was prepared from 2,3,5,6,7,8-hexahydro-3,5,5,8,8-pentamethyl-cyclopenta[b]naphthalen-1-one. The preparation ofthe above naphthalen-1-one is shown below. Friedel-Crafts alkylation of crotonic acid with 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in the presencé ~ minl~m trichloride gave the corresponding enone, which was then cyclized to the naphthalen-1-one using PPA at 110~C for 3h). Procedures similar to those in Examples 10 and 11 afforded the compound 107b: RfO.25 (40% ether in hexane); mp 216-218~C; lH NMR (400 MHz, CDCl3) d: 7.66(s, lH, ArH), 7.54(dd, J=15.1, 11.6Hz, lH, olefinic), 7.22(s, lH, ArH), 6.31(d, J=15.1 Hz, lH, olefinic), 6.27(d, J=11.6 Hz, lH, olefinic), 5.82(s, lH, olefinic), 3.20(m, lH), 2.99(m, lH, allylic), 2.42(m, 4H, CH3, allylic), 1.71(s, 4H, 2CH2), 1.33(m, 6H, 2CH3), 1.30(m, 9H, 3CH3).

Preparation of compound 108b accordin~ to Scheme II
(2E,4E)-3-Methyl-6-[(Z)- 3,5,6,7-tetrahydro-5,5,7,7-tetramethyl-2~:-5-indacen-1-ylidene]hexa-2,4-dienoic acid (structure 6, where R1, R2, R3, R4, and Rlg are methyl;
25 Rs, R6, R7, Rg, Rg and R1o are hydrogen; R1s is hydroxy; X, Y and Z are carbon; m = n =O) The title acid was prepared from 5,5,7,7-tetramethyl-3,5,6,7-tetrahydro-2H-5-indacen- 1 -one using procedures similar to those of Examples 10 and 11. The above indacen-1-one was prepared in a manner similar to that of 1,2,3,6,7,8-hexahydro-1,1,3,3-30 tetramethyl-cyclopenta[b]naphthalene-5-one in Example 5, except that indane was DOCKET NO. CA 02209134 1997-06-27 , 016-OOlgA.WO

employed as the starting material. The title compound 108b had Rf=0.35 (50~/0 ether in hexane); mp 159-161~C; lHNMR (400 MHz, CDC13) d: 7.52(dd, J=15.4, 12.9 Hz, lH, olefinic), 7.43(s, lH, ArH), 7.06(s, lH, ArH), 6.31(d, J=15.4 Hz, lH, olefinic), 6.28(d, ~ J=12.9 Hz, IH, olefinic), 5.83(s, lH, olefinic), 2.95(m, 2H, CH2~ benzylic), 2.88(m, 2H, CH2, allylic), 2.40(s, 3H, CH3), 1.96(s, 2H, CH2), 1.34(m, 6H, 2CH3), 1.32(s, 6H, 2CH3).

Preparation of compound 109a according to Scheme III
Ethyl (2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-he~ahydro-5,5,8,8-tetramethyl-2E~-anthracen-1-ylidenelhe~a-2,4-dienoate (structure 7, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, Rg, Rg, R1o are hydrogen; R15 is ethoxy; X, Y, and Z are carbon; m = n=l).
To a solution of 3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-l-one (512 mg, 2 mmol, from Example 1) in MeOH~10 ml) was added NaBH4 (76 mg, 2 mmol) at 0~C. The reaction mixture was stirred at that temperature for 30 min, then quenched with sat. aqueous NH4CI (5 ml), extracted with ether (50 ml), dried (MgSO4), and concentrated under reduced pressure to give the corresponding tricyclic alcohol, which was used without further purification. To the above alcohol (516 mg, 2 mmol) in MeOH (5 ml) was added Ph3P-HBr (686 mg, 2 mmol) at 25~C. The mixture was heated at 85~C for 5 h. Removal of the solvent, followed by addition of hexane (100 ml) gave a white solid, which was then filtered to give pure 3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-triphenylphosphonium bromide (697 mg, 60%).
To a solution ofthe above phosphonium salt (581 mg, 1 mmol) in THF (8 ml) was added nBuLi (0.4 ml, 2.5 M, 1 mM) at 0~C and the reslllting dark-red solution was stirred at that temperature for 30 min to afford the ylide. To this freshly prepared ylide was added ethyl (2E,4E)-3-methyl-5-formylpenta-2,4-dienoate. [The ethyl dienoate was prepared by the condensation of ethyl-3-methyl-4-oxocrotonate and (triphenylphosphoranylidene)acetaldehyde in benzene at 85~C for 3 h using benzoic acid as a catalyst (168 mg, 1 mmol) in THF(5 ml) at 0~C, and the resulting mixture was stirred at DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

,- this temperature for 30 min.] The reaction mixture was quenched with NH4CI (10 ml), extracted with ether (50 ml?, dried(MgS04), concentrated, and purified by chromatography (10% ether in hexane) to give the pure title compound lO9a (372 mg, 95%): RfO.52 (10% ether in hexane); lH NMR(400 MHz, CDC13) ~ 7.58 (s, lH, ArH), 7.04 (dd, J=11.2, 15.0 Hz, lH, olefinic), 7.02 (s, lH, ArH), 6.69 (d, J=11.2 Hz, lH, olefinic), 6.39 (d, J=15.0 Hz, lH, olefinic), 5.79 (s, lH, olefinic), 4.16 (q, 2H, OCH2), 2.75 (t, J=6.1 Hz, 2H, CH2, benzylic), 2.68 (t, J=5.9 Hz, 2H, CH2~ allylic), 2.36 (s, 3H, CH3), 1.85 (m, 2H, CH2), 1.65 (s, 4H, 2cH2)~ 1.31 (s, 6H, 2CH3), 1.25 (m, 9H, 3CH3).

Preparation of compound 109b accordin~ to Scheme III
(2E,4E)-3-Methyl-6-[(E)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2:~-anthracen- l-ylidene]hexa-2,4-dienoic acid (structure 7, where R1, R2, R3, R4, and R1g are methyl, Rs, R6, R7, Rg, Rg, and Rlo are hydrogen, Rls is hydroxy, X, Y, and Z are carbon, m =
n = 1).
The title acid was prepared from hydrolysis of compound lO9a using the standard conditions employed in Example 2. Compound 109b had RfO.25 (50% ether in hexane), mp 230 - 231 ~C; lH NMR (400 MHz, CDCl3) ~ 7.60(s, lH, ArH), 7.09(dd, J=1.2, 15.0 Hz, lH, olefinic), 7.03(s, lH, ArH), 6.70 (d, J=11.2 Hz, lH, olefinic), 6.43 (d, J=15.0 Hz, lH, olefinic), 5.82 (s, lH, olefinic), 2.77 (t, J=6.1 Hz, 2H, CH2, benzylic), 2.70 (t, J=5.9 Hz, 2H, CH2, allylic), 2.37 (s, 3H, CH3), 1.86 (m, 2H, CH2), 1.67 (s, 4H, 2CH2), 1.31 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3).
.EXAMPLE 16 Preparation of compound l lOa according to Scheme III
Ethyl (2E,4E)-3-methyl-6-[(E)-2,3,5,6,7,8-he~ahydro-5,5,8,8-tetramethyl-cyclopenta[b]naphthalen-l-ylidene]hexa-2,4-dienoate (structure 7, where R1, R2, R3, B4, and Rlg are methyl; Rs, R6, R7, Rg, Rg, and Rlo are hydrogen; R15 is ethoxy; X, Y, and Z are carbon; m = 1, n = O).
The title compound was prepared in a manner similar to that of compound 59a except that 2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]-1-one [US patent DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO
. . . ~ _ 2.815.38~2 (1957)] was used in place of 3,4,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-one for the NaBH4 reduction step in Example 14. Compound 110a had mp 128 - 129~C, lH NMR(400 M:Hz, CDC13) ~ 7.47 (s, lX ArH), 7.23 (s, lH, ArH), 6.85 (dd, J=11.3, 15.2 Hz, lH, olefinic), 6.62 ~d, J=11.3 Hz, lH, olefinic), 6.31 (d, J=15.2 Hz, lH, olefinic), 5.75 (s, lH, olefinic), 4.17 (q, 2H, OCH2~ 3.05-2.85 (m, 4H, 2CH2, benzylic and allylic), 2.45 (s, 3H, CH3), 1.65 (s, 4H, CH2)~ 1.28 (s, 6H, 2CH3), 1.27 (m, 9H, 3CH3).

Preparationofcompound 110b accordin~to SchemeIII
(2E,4E)-3-Methyl-6-~(E)-2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-cyclopenta[b]naphthalen-l-ylidene]hexa-2,4-dienoic acid (structure 7, where Rl, R~, R3, R4, and Rlg are methyl; R5, R6, R7, Rg, Rg, and Rlo are hydrogen; R1s is hydroxy;
X, Y, and Z are carbon; m = 1, and n = 0).
The title acid was prepared by hydrolysis of compound 110a using the standard hydrolysis conditions in Example 2. Compound 110b had mp 200-202~C, lH NMR (400 MHz, CDC13) ~ 7.47 (s, lH, ArH), 7.23 (s, lX ArH), 6.92 (dd, J=11.3, 15.1 Hz, lH, olefinic), 6.63 (d, J=11.3 Hz, lH, olefinic), 6.35 (d, J=15.1 Hz, lH, olefinic), 5.79 (s, lH, olefinic), 3.02-2.91 (m, 4H, 2CH2, benzylic and allylic), 2.37 (s, 3H, CH3), 1.67 (s, 4H, 2CH2), 1.30 (s, 6H, 2CH3), 1.27 (s, 6H, 2CH3).

Preparation of compound llla accordin~ to Scheme III
Ethyl (2E,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-25 tetramethylcyclopenta[blnaphthalen-5-ylidene]hexa-2,4-dienoate (structure 7, where Rl, R2, R3, R4, and Rlg are methyl; R5, R6, R7, Rg, Rg, and Rlo are hydrogen; Rls is ethoxy; X, Y, and Z are carbon; m=0, and n=l).
The tiile compound was prepared in a manner similar to that of compound 59a except that 1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-1-one (the 30 preparation ofthe title ketone is described in example 5) was used as the starting ketone in DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

the NaBH4 reduction step of Example 14. Compound 111a had RfO.84 (10% ether in hexane); lH NMR (400 MHz, CDC13) o 7.4 (s, lH, ArH), 7.07 (dd, J=15.0, 11.3 Hz, lH, olefinic), 6.86 (s, lH, ArH), 6.75 (d, J=l 1.3 Hz, lX olefinic), 6.42 (d, J=15.0 Hz, lH, olefinic), 5.81 (s, lH, olefinic), 4.15 (q, 2H, OCH2), 2.82 (t, J=6.0 IIz, 2X CH2, benzylic), 2.73 (t, J=5.71 Hz, 2X CH2~ allylic), 2.38 (s, 3H, CH3), 1.91 (s, CH2, 2H), 1.89 (m, 2X CH2), 1.32 (s, 6H, 2CH3), 1.30 (m, 9H, 3CH3).

Preparation of compound l l lb accordin~ to Scheme III
(2E,4E)-3-Methyl-6-1(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]-5-ylidenelhexa-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4, and Rlg are methyl, R5, R6, R7, Rg, Rg, and Rlo are hydrogen, R15 is hydroxy, X, Y, and Z are carbon, m=0, and n=1) The title compound was prepared from hydrolysis of ester 111a using the standardhydrolysis conditions employed in Example 2. Acid 111b had RfO.40 (30% ether in hexane), mp 207-209~C, lH NMR (400 MHz, CDC13) ~ 7.41 (s, lH, ArH), 7.10 (dd, J=15.0, 11.3 Hz, lH, olefinic), 6.87 (s, lH, ArH), 6.77 (d, J=11.3 Hz, lH, olefinic), 6.45 (d, J=15.0 H:z, lH, olefinic), 5.84 (s, lH, olefinic), 2.83 (t, J=6.0 Hz, 2H, CH2, benzylic), 2.73 (t, J=5.7 Hz, 2X CH2, allylic), 2.40 (s, 3H, CH3), 1.91 (s, 2H, CH2), 1.88 (m, 2H, CH2), 1.34 (s, 6H, 2CH3), 1.30 (s, 6H, 2CH3).

Preparation of compound 112a accordin~ to Scheme I & III
Ethyl (2Z,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopentalb~naphthalen-5-ylidenelhexa-2,4-dienoate (structure 7, where Rl, R2, R3, R4, and Rlg are methyl; R5, R6, R7, R8, Rg, and Rlo are hydrogen; Rls is ethoxy; X, Y, and Z are carbon; m=0, and n=l) The title compound was obtained as a by-product from the preparation of compound 111a of Example 18. Compound 112a had Rf-0.85 (10% ether in hexane); lHNMR (400 MHz, CDC13) ~ 7.92 (d, J=15.2 Hz, IH, olefinic), 7.46 (s, lH, ArH), 7.12 (dd, DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

J=15.2, 11.2 Hz, lH, olefinic), 6.90 (d, J=11.2 Hz, lH, olefinic), 6.86 (s, lH, ArH), 5.82 (s, lH, olefinic), 4.20 (q, 2H, OcH2)~ 2.90 (t, J=5.9 Hz, 2H, CH2, benzylic), 2.75 (t, J=5.7 Hz, 2H, CH2, allylic), 2.10 (s, 3H, CH3), 1.95 (s, 2H, CH2)~ 1.93 (m, 2X CH2,), 1.32 (s, 6H, 2CH3), 1.30 (m, 9H, 3CH3).

Preparation of compound 112b according to Scheme I
(2Z,4E)-3-Methyl-6-1(E)-1,2,3,6,7,8-h-exahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoic acid (structure 7,where R1, R2, R3, R4, and R1g are methyl; R5, R6, R7, Rg, Rg, and R1o are hydrogen;
Rls is hydroxy; X, Y, and Z are carbon; m=O, and n=l) - The title compound was prepared from hydrolysis of compound 112a using the standard hydrolysis conditions described in Example 2. Compound 112b had RfO.50 (30% ether in hexane); lH NMR (400 M:Hz, CDCl3) o 7.85 (d, J=15.2 Hz, lH, olefinic), 7.46 (s, lH, ArH), 7.12 (dd, J=15.2, 11.3 Hz, lH, olefinic), 6.90 (d, J=11.3 Hz, lH, olefinic), 6.86 (s, lH, ArH), 5.69 (s, lH, olefinic), 2.82 (t, J=6.1 Hz, 2H, CH2, benzylic), 2.23 (t, J=5.9 Hz, 2H, CH2, allylic), 2.14 (s, 3H, CH3), 1.91 (s, 2H, CH2), 1.89 (m, 2H, CH2), 1.25 (s, 6H, 2CH3), 1.22 (s, 6H, 2CH3).

Preparation of compound 113b accordin~ to Scheme II
(2E,4E)-3-Methyl-6-[(E)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2~I-anthracen-1-ylidene]hexa-2,4-dienoic acid (structure 7, where R1, R2, R3, R4, and R1g are methyl; Rs, R6, R7, Rg, Rg, and R1o are hydrogen; R1s is hydroxy; X and Y are carbon; Z is C(CH3)2; m=n=1).
This compound was prepared starting from 2-[(E)-3,4,5,6,7,8-hexahydro-2H-4,4,5,5,8,8-hexamethylanthracene-1-ylidine] ethanol as described for the (2E,4E,6Z)-isomer (Examples 10 and 11). Compound 113b had: 1H NMR (400 MHz, CDC13) o 7.59 (s, 1 H, Ar); 7.08 (d J=12 Hz, lH,), 7.0 (s, lH, Ar), 6.7 (d, J=12 Hz, lH), 6.28 (d, J=12 DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

~ 61 Hz, iH), 5.82 (s~ lH), 2.7 (t, J=4.5 Hz, 2H), 2.37 (s, 3H, CH3), 1.68 (t, J=4.0 Hz, 2H), 1.66 (s, 4H), 1.3 (s, 18H).

5 Preparation of compounds 114a according to Scheme I
Ethyi (2E,4E,6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]he~a-2,4,6-trienoate (structure 7 where Rl, R2, R3, R4 and R1g are methyl, R5, R6, R7, Rg, Rg, and R1o are hydrogen; R1s is ethoxy; X Y and Z are carbon; m=1 and n =2).
The title ester was prepared from 1-benzosuberone (Aldrich) according to Scheme I following the representative procedure for compounds 59a and 59b as outlined in Examples 14 and 15. Compound 114a had Rf 0.5 (5% EtOAc-hexanes); 1H-NMR (400 MHz, CDCl3) ~ 7.11 (s, lH, ArH), 7.00 (s, lH, ArH), 6.99 (m, lH, olefinic), 6.33 (d, J=16 Hz,lH, olefinic), 6.21 (d, J=16 Hz,lH, olefinic), 5.80 (s, lH, olefinic), 4.20 (m, 2H, -OCH2CH3), 2.67 (d, J=16 Hz, 4H, 2CH2), 2.39 (s, 3H, CH3), 1.78 (s, 4H, 2CH2), 1.68 (s, 4H, 2CH2), 1.33 (m, 15H, 4CH3; -CH2CH3).

Preparation of compound 114b according to Scheme I
(2E,4E,6E)-3-Methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6I~-naphthocycloheptene-10-yllhe~a-2,4,6-trienoic acid. (structure 7 where R1, R2, R3, R4 and R1g are methyl; Rs, R6, R7, Rg, Rg, and R1o, are hydrogen; Rls is hydroxy; X, Y
and Z are carbon; m=1 and n =2).
The title compound was prepared from ester 114a following the standard hydrolysis procedure as outlined in Example 2. Compound 114b had RfO.3 (15%
EtOAc-hexanes); mp 244-246~C; 1H-NMR (400 MHz, CDC13) ~ 7.12 (s, lH, ArH), 7.02 (m, lH, olefinic), 7.00 (s, lH, ArH), 6.38 (d, J=16 Hz, 1X olefinic), 6.25 (d, J=16 Hz, lH, olefinic), 5.85, (s, lH, olefinic), 2.72 (t, J=16 Hz, 2X CH2), 2.62 (t, J=16 Hz, 2H, CH2), 2.40 (s, 3H, CH3), 1.80 (m, 4H, 2CH2), 1.68 (s, 4H, 2CH2), 1.31 (s, 6H, 2CH3), 1.30 (s, 6H, 2CH3).

DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 115a according to Scheme I
Ethyl (2Z,4E,6E)-3-methyl-6-11,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoate (Structure 7, where Rl, R2, R3, R4 and Rlg are methyl, R5, R6, R7, R8, Rg, and Rlo are hydrogen; R15 is ethoxy; X, Y and Z are carbon; m=l and n=2).
The title compound was prepared as a by-product from the synthesis of compound 114a (Example 23). The title compound 115a had RfO.3 (15% EtOAc-hexanes); lH-N~. (400 MHz, CDC13-) o 7.82 (d, J=16 Hz, lH, olefinic), 7.12 (s, lH, ArH)., 7.00 ~s, lH, ArH), 6.38 (d, J=16 Hz,lH, olefinic), 5.68 (s, lH, olefinic), 4.15 (q, J=8 Hz, 2H, -OCH2CH3), 2.65 (d, J=16 Hz, 4H, 2CH2), 2.28 (s, 3H, CH3), 1.72 (s, 4H, 2CH2), 1.68 (s, 4H, 2CH2), 1.23 (s, 6H, 2CH3), 1.27 (s, 6H, 2CH3), 0.9 (t, J=8 Hz, 3H, -OCH2CH3).

Preparation of compound 115b accordin~ to Scheme I
(2Z, 4E, 6E)-3-Methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6~I-naphthocycloheptene-10-yl~hexa-2,4,6-trienoic acid (structure 7, where Rl, R2, R3, R4, and Rlg are methyl; R5, R6, R7, Rg, Rg and Rlo are hydrogen; Rls is ethoxy; X, Y
20 and Z are carbon; m = 1 and n = 2).
The title acid was prepared ~om ester 115a using the hydrolysis procedure outlined in Example 2. Compound 115b had RfO.5 (10% MeOH-CHCl2); lH-NMR (400 MHz, CDCl3) o 7.76 (d, J=16 Hz,lH, olefinic), 7.11 (s, lH, ArH)., 7.04 (m,lH, olefinic), 6.99 (s, lH, ArH), 6.32 (d, J=16 Hz, lH, olefinic), 5.69 (s, lH, olefinic), 2.65 (d, J=16 Hz, 4H, 2CH2), 2.10 (s, 3H, CH3), 1.65 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.31 (s, 6H, 2CH3).

Preparation of compound 116b accordin~ to Scheme I
(2E,4E)-3-Methyl-6-[(E)-3,5,6,7-tetrahydro-5,5,7,7-tetramethyl-2H-5-indacen-1-ylidene]hexa-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4, and Rlg are methyl;

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Rs, R6, R7, R8, Rg and R1o are hydrogen; R15 is hydroxy; X, Y and Z are carbon, m = n =0).
The title acid was prepared from 5,5,7,7-tetramethyl-3,5,6,7-tetrahydro-2H-5-indacen-l-one in a manner similar to that of compound 59b in Example 14. Compound 116b had Rf~0.36 (50% ether in hexane), amorphous material; lH NMR(400 MHz, CDCl3) ~: 7.27 (s, lH, ArH), 7.02 (s, lH, ArH), 6.92 (dd, J=15.1, 12.5 Hz, lH, olefinic), 6.68 (a, J=12.5 Hz, lH, olefinic), 6.35 (d, J=15.1 Hz, lH, olefinic), 5.89 (s, lH, olefinic), 3.02 (m, 2H, CH2), 2.98 (m, 2H, CH2)~ 2.38 (s, 3H, CH3), 1.94 (s, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.30 (s, 6H, 2CH3).

Preparation of compound 117a accordin~ to Scheme I
Ethyl (2E,4E)-3-methyl-6-l(E)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-l-ylidene]he~a-2,4-dienoate (structure 7, where Rl, R2, R3, R4, and R1g are methyl; R5, R6, R7, Rg, and R1o are hydrogen; Rg is nitro; R1s is ethoxy, X, Y, Z are carbon, m=n= 1).
The title compound was prepared from 10-nitro-1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-one (of Example 8) using a procedure similar to that described in Example 1. Compound 117a was obtained as a yellow oil: 1H NMR (400 MHz, CDC13) o 7.72 (s, lH, aromatic), 7.01 (dd, J=15.1, 11.2 Hz, lH, olefinic), 6.72 (d, J=11.2 Hz, lH, olefinic), 6.46 (d, J=15.1 Hz, lH, olefinic), 5.84 (s, lH, olefinic), 4.19 (q, J=7.1 Hz, 2H, -OCH2), 2.67 (br t, J=5.6 Hz, 2H, CH2), 2.55 (t, J=6.3 Hz, 2H, CH2), 2.37 (d, J=1 0 Hz, 3H, CH3 allylic), 1.85 (app quintet, J=6.3 Hz, 2H, CH2), 1.75 (m, 2H, CH2), 1.67 (m, 2H, CH2), 1.35 (s, 6H, 2CH3), 1.32 (s, 6H, 2CH3), 1.30 (t, J=7.1 Hz, 3H, CH3 ethyl).

Preparation of compound 117b accordin~ to Scheme I
(2E,4E)-3-Methyl-6-[(E)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-213 -anthracen-l-ylidene]he~a-2,4-dienoic acid (structure 7, where R1, R2, R3, R4, and R1g DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

are methyl; Rs, R6, R7, R8, and Rlo are hydrogen; Rg is nitro; R15 is hydroxy, X, Y, Z
are carbon, m = n= 1).
The title acid was prepared from compound 117a using standard hydrolysis conditions outlined in Example 2. Compound 117b was obtained as a yellow solid (75%
yield): lH NMR (400 MHz, CDC13) o 7.73 (s, lH, aromatic), 7 02 (br t, lH, olefinic), 6.70 (d, J=11.1 Hz, lH, olefinic), 6.49 (d, J=14.9 Hz, lH, olefinic), 5.86 (s, lH, olefinic), 2.68 (br t, 2H, CH2), 2.55 (br t, 2H, CH2), 2.36 (s, 3H, CH3 allylic), 1.86 (m, 2H, CH2), 1.74 (m, 2H, CH2), 1.69 (m, 2H, CH2), 1 35 (s, 6H, 2CH3), 1.32 (s, 6H, 2CH3).
.

Preparation of compound 118b accordin~ to Scheme I
(2Z,4E)-3-Methyl-6- [(E)-3,4,5,6,7,8-he~ahydro-10-nitro-5,5,8,8-tetramethyl-2}I-anthracen-1-ylidenelhexa-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, Rg, and R1o are hydrogen; Rg is nitro; Rls is hydroxy, X, Y, Z
are carbon, m = n = 1).
Obtained as a by-product from synthesis of compound 117a (Example 28) after hydrolysis of the ester using conditions outlined in Example 2. Compound 118b had lH
N~ (400 MHz, CDC13) o 7.91 (d, J=15.2 Hz, lH, olefinic), 7.74 (s, lH, aromatic), 7.02 (br t, lH, olefinic), 6.81 (d, J=11 4 Hz, lH, olefinic), 5.78 (br s, lH, olefinic), 2.67 (br t, J=6.2 Hz, 2H, CH2), 2.55 (t, J=6.2 Hz, 2H, CH2), 2.11 (s, 3H, CH3 allylic), 1.85 (m, 2H, CH2), 1.74 (m, 2H, CH2), 1.68 (m, 2H, CH2), 1.35 (s, 6H, 2CH3), 1.32 (s, 6X 2CH3).

DOCKETNO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 119b according to Scheme I and Scheme IV
(2E,4E)-3-Methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-benzo[g]~hromen-4-ylidene]he~a-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4, and R1g are methyl; Rs, R6, R7, Rg, Rg, Rlo are hydrogen; R15 is hydroxy; X and Y are carbon; Z is oxygen; m= n= 1).
In a manner sirnilar to that described in Example 7 above, an isomeric mixture of (E, Z)-(chromen-4-ylidene)acetonitrile (550mg, 3.5 mmol) was converted to (E)-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-ylidene)acetonitrile. Flash chromatography (20% EtOAc/hexanes) of the crude brown solid gave the tricyclic nitrile as a light yellow solid (511 mg 1.82 mmol, 52%): H NMR (400 MHz, CDC13) o 7.4 (s, lH), 6.82 (s, lH), 5.7 (s, lH ), 4.25 (t, 2H), 3.0 (t, 2H), 1.67 (s, 4H), 1.26 (s, 6H), 1.24 (s, 6H).
The tricyclic nitrile (1.85 g, 6.6 mmol) was then converted to (E)-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-ylidene)acetaldehyde using CH2C12 as solvent in place of THF. The crude brown oil was purified by flash chromatography (20%
EtOAc/hexane) to give the aldehyde as a yellow/orange solid (640 mg, 2.3 mmol, 40%):
H NMR (400 MHz, CDC13) o 10.12 (d, lH ), 7.6 (s, lH), 6.82 (s, lH), 6.55 (d, lH), 4.30 (t, 2H), 3.25 (t, 2H), 1.68 (s, 4 H ), 1.25 (s, 12H).
The tricyclic aldehyde (640 mg, 2.2 rnmol) was then transformed to a mixture of ethyl (2E,4E)- and (2Z,4E)-3-methyl-6-[(E) 2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-benzo[g]chromen-4-ylidene]hexa-2,4-dienoates. NaH was used in place of n-BuLi and 2 equivalents of phosphonate and base were used. The aldehyde was added at 0~C andwarmed to 15~C over 1 h. Aqueous work up (and Et2O extraction) gave the esters as a yellow oil (820 mg, 2.08 mmol, 93%). Flash chromatography (8% EtOAc/hexane) gave the trans -isomer as a yellow solid (191 mg): lH NMR (400 MHz, CDC13) ~ 7.55 (s, lH), 6.95 (dd, lH), 6.8 (s, lH), 6.72 (d, lH), 6.42 (d, lH ), 5.80 (s, lH ), 4.20 (m, 4H), 2.8 (t, 2H), 2.36 (s, 3H ), 1.68 (s, 4 H), 1.3 (t, 3H ), 1.27 (s, 12H ).
Using the procedure of Example 7, the above ester (191 mg, 0.48 mmol) was converted into the title acid. Compound 119b was obtained as a yellow solid (168 mg, 45 DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

mrnol, 96%): TLC Rf=0.20 (40% Et2olHexane); mp 198.2~C, lH NMR (400 MHz, CDC13) o 7.55 (s, lH), 6.95 (dd, lH), 6.8 (s, lH), 6.72 (d, lH), 6.42 (d, lH), 5.80 (s, lH), 4.20(m, 2H), 2.8 (t, 2H), 2.36 (s, 3H), 1.68 (s, 4H), 1.27 (s, 12H).

Preparation of compound 120b according to Schemes II and IV
(2Z,4E)-3-Methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-ylidene]hexa-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4, and Rlg are methyl;
Rs, R6, R7, Rg, Rg, Rlo are hydrogen; R15 is hydroxy; X and Y are carbon; Z is oxygen;
10 m = n = 1).
The isomeric mixture of esters described above in Example 31 was purified by flash chromatography (8% EtOAc/hexane) to give ethyl(2Z,4E)-3-methyl-6-[(E) 2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-benzo[g]chromen-4-ylidene]hexa-2,4-dienoate as a yellow oil (131 mg): lH NMR (400 MHz, CDC13) ~ 7.95 (d, lH), 7.58 (s, lH), 6.95 (dd, lH), 6.85(d, lH),6.80(s, lH),5.67(s, lH),4.20(m,4H),2.8(t,2H),2.10(s,3H), 1.68(s,4 H), 1.3 (t, 3H), 1.27 (s, 12H).
Employing the procedure described in Example 2, the above ester (131 mg, 0.33 mmol) was converted to the title acid. Acid 120b was obtained as a yellow oily solid (108mg, 29.7 mmol, 90%): TLC RfO.28 (40% Et20/Hexane); lH NMR (400 MHz, CDC13) ~ 7.95 (d, lH), 7.58 (s, lH), 6.95 (dd, lH), 6.85 (d, lH), 6.80 (s, lH), 5.67 (s, lH), 4.20~m, 2H), 2.8 (t, 2H), 2.10 (s, 3H), 1.68 (s, 4 H), 1.27 (s, 12H).

Preparation of compound 121b accordin~ to Schemes I and II
(2E,4E)-3-Methyl-6-[(E)-2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-he~amethyl-benzolg]chromen-4-ylidenelhexa-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4, R7, Rg, and Rlg are methyl; Rs, R6, R9, Rlo are hydrogen; R15 is hydroxy; X and Y are carbon; Z is oxygen; m= n= 1).
Using the procedure described in Example 31, 2-[(E)-3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethylnaphtho-(2,3-b)-1,2 pyran-4-ylidene]ethanitrile (500 mg, 1.6 mmol) DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

was reduced with DIBAL in CH2cl2 to give the corresponding aldehyde. Aqueous work up gave 2-(E)-[3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethylnaphtho-(2,3-b)-1,2-pyran-4-ylidene]acetaldehyde which was purified by flash chromatography (8% EtOAc/hexane) to ~ ~ afford a light yellow solid (220mg, 0.71 mmol, 45% yield): lH NMR (400 MHz, CDCl3) o 10.1 (d, lH), 7.52 (s, lH), 6.8 (s, lH), 6.60 (d, lH), 3.05 (s, 2H) ,1.70 (s, 4H), 1.4 (s, 6H), 1.25 (s, 12H).
The above aldehyde was converted to the corresponding triene ester in a manner similar to that described in Example 23. Aqueous work up gave a yellow oil which partially solidified on standing. Flash chromatography (20% EtOAc/hexane) afforded ethyl (2E,4E)-3-methyl-6-[(E~-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthyl (2,3-b ) 2,2-dimethylpyran-4-yl]hexa-2,4-dienoate as a bright yellow solid (115 mg, 0.27 mmol, 83%
yield): lH NMR (400 M:Hz, CDC13) o 7.50 (s, lH), 6.95 (dd, lH), 6.75 (m, 2H), 6.45 (d, lH), 5.8 (s, lH), 4.10 (m, 2H), 2.66 (s, 2H), 2.39 (s, 3H), 1.65 (s, 4H), 1.33 (s, 6H), 1.31 (t, 3H), 1.30 (s, 6H), 1.25 (s, 6H).
The above ester (60.5mg, 0.143 mmol) was hydrolyzed to the corresponding acid using the procedure described in Example 2 to give the title compound as a bright yellow solid (50mg, 0.127 mmol , 88%): TLC Rf=0.10 (20% EtoAc/Hexane); mp 224~C; lH
NMR (400 M~Iz, CDC13) ~ 7.50 (s, lH), 7.02 (dd, lH), 6.79 (d, lH), 6.75(s, lH), 6.50 (d, lH), 5.87 (s, lH), 2.66 (s, 2H ), 2.40(s, 3H ), 1.68(4s, H), 1.38(s, 6H), 1.30 (s, 6H), 1.25 (s, 6H).

Preparation of compound 122a according to Scheme V
Ethyl (2E,4E)-3-methyl-6-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoate (structure 20, where R1, R2, R3, R4, and R1g are methyl; Rs, R7, Rg, Rg, and R1o are hydrogen; R15 is ethoxy; X, Y, and Z are carbon; m = n = 1).
To a solution of trimethyl phosphonoacetate (5.68 g, 31 mmol) in THF (15 ml) was added dropwise nBuLi (9.3 ml, 2.5 M, 23 mM) at 0~C, and the resulting solution was stirred at that temperature for 30 min. 3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-30... anthracen-1-one (2.0 g, 7.8 mmol) in T~ (10 ml) was added at 25~C, and the mixture was DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

stirred at that temperature for 30 min. Standard work-up procedures as detailed in Example 1, followed by purification of the product by colurnn chromatography (10 % ether in hexane) gave methyl (3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)acetate (1.33 g, 55%): lH NMR(400 MHz, CD(~13) ~ 7.15 (s, lH, ArH), 7.04 (s, lH, ArH), 5.94 (br t, lH, olefinic), 3.68 (s, 2H, OCH3), 3.43 ~s, 2H, CH2)~ 2.74 (t, J=7.9 Hz, 2H, CH2, benzylic), 2.31 (m, CH2, 2H, allylic), 1.66 (s, 4H, 2CH2), 1.27 (s, 12H, 4CH3).
To a solution ofthe above methyl ester (312 mg, 1 mmol) in CH2C12 (5 ml) was added dropwise DIBAL (1 ml, 1 M, 1.0 rnM) at -78~C. The resulting mixture was stirred at -78~C for 30 min, then warmed to room temperature, followed by standard work-up procedure as described in Example 1. Purification ofthe corresponding aldehyde by chromatography (10 % ether in hexane) gave pure (3,4,5,6,7,8-hexahydro-5,5,8,8-teramethylanthracen-l-yl)-acetaldehyde (140 mg, 50 %): lH NMR(400 MHz, CDC13) 9.64 (t, J=2.6 Hz, lH, CHO), 7.07 (s, lH, ArH), 7.03 (s, lH, ArH), 5.98 (br t, lH, olefinic), 3.44 (s, 2H, CH2), 2.77 (t, J=7.9 Hz, 2H, CH2, benzylic), 2.35 (m, 2H, CH2, allylic), 1.66 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3).
The above aldehyde was coupled with the anoin of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate, as described for compound 51a in Example 1, to give the title compound 122a: RfO.25 (10% ether in hexane) lH NMR(400 MHz, CDC13) ~ 7.15 (s, lH, ArH), 7.09 (s, lH, ArH), 6.07 (m, 2H, olefinic), 5.85 (s, lH, olefinic), 5.65 (br t, lH, olefinic), 4.02 (q, 2H, OCH2), 3.12 (br d, 2H, CH2, allylic), 2.61 (t, J=7.8 Hz, 2H, CH2, benzylic), 2.30 (s, 3H, CH3), 2.09 (m, 2H, CH2, allylic), 1.60 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3), 0.98 (t, J=7.0 Hz, 3H, CH3).

Preparation of compound 122b according to Scheme V
(2E,4E)-3-Methyl-6-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)-hexa-2,4-dienoic acid (structure 20a, where Rl, R2, R3, R4, and R1 9 are methyl; Rs, R7, Rg, Rg, and R1o are hydrogen; Rls is hydroxy; X, Y, and Z are carbon; m = n = 1).
The title compound was prepared by hydrolysis of compound 122a using the standard conditions described in Example 2. Compound 122b had mp. 171-173~C, lH

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

NMR (400 MHz, CDC13) ~ 7.15 (s, lH, ArH), 7.06 (s, lH, ArH), 6.26 (m, 2H, olefinic), 5.81 (brt, lH, olefinic), 5.74 (s, lH, olefinic), 3.30 (br s, 2H, CH2, allylic), 2.72 (t, J=8.0 - Hz, 2H, CH2, benzylic), 2.27 (m, 2H, CH2, allylic), 2.26 (s, 3H, CH3), 1.66 (s, 4H, 2CH2), 1.25 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).

Preparation of compound 123b accordin~ to Scheme V
(3E,5E)-3-Methyl-6-(3,4,5,6,7,8-he~ahydro-5,5,8,8-tetramethylanthracen-1-yl)he~a-3,5-dienoic acid (structure 20b, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, 10 Rg, Rg, and Rlo are hydrogen; R15 is hydroxy; X, Y, and Z are carbon; m= n=1) The title compound was prepared as a by-product from the hydrolysis of compound 122a of Examples 34 and 35. Compound 123b had RfO.30 (50% ether in hexane); mp 183-185~C; 1H NMR: (400 MHz, CDC13) ~ 7.32 (s, lH, ArH), 7.10 (s, lH, ArH), 7.07 (d, J=10.8 Hz, lH, olefinic), 6.78 (dd, J=15.8, 10.8 Hz, lX olefinic), 6.43 (d, J=15.8Hz, lX olefinic), 6.15 (brt, lH, olefinic), 3.15 (s, 2H, CH2, a-methylene), 2.69 (t, J=7.5 Hz, 2H, CH2, benzylic), 2.30 (m, 2H, CH2, allylic), 1.90 (s, 3H, CH3), 1.68 (s, 4H, 2CH2), 1.3 0(s, 6H, 2CH3), 1.29 (s, 6H, 2CH3).

Preparation of compound 124a according to Scheme VI
Ethyl (2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)-hexa-2,4-dienoate (structure 22, where R1, R2, R3, R4, and R1g are methyl; Rs, R6, R7, Rg, Rg, and R1o are hydrogen; R15 is ethoxy; X, Y, and Z are carbon; m = n=1).
To a solution of [(E)-3,4,5,6,7,8,9-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]ethanitrile (56 mg, 0.2 mmol from Example 1) in EtOAc (5 ml) was added 5 mg of 10% Pd-C catalyst, and the reaction rnixture was treated with hydrogen gas at 1 atm for 3 h. Removal of the catalyst by filtration, and concentration of organic solvent gave essentially pure saturated nitrile which was used for the next reaction without further purification. The saturated nitrile was then sequentially subjected to DIBAL reduction and Wittig coupling reaction using conditions similar to those described in Example 1 to afford, DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

after column chromatography, the title compound 124a: RfO.55(10 % ether in hexane);
lH NMR(400 MHz, CDCl3) ~ 7.09 (s, lH, ArH), 6.98 (s, lH, ArH), 6.20 (m, lH, olefinic), 6.12 (d, J=15.7 Hz, lH, olefinic), 5.70 (s, lH, olefinic), 4.13 (q, 2H, OCH2), 2.85 (m, lH, CH), 2.79 (br t, 2H, CH2~ benzylic), 2.60 (m, lH, CH, allylic), 2.37 (m, lH, CH, allylic), 2.30 (s, 3H, CH3), 1.80 (m, 2X CH2~ methylene), 1.65 (m, 2H, CH2, methylene), 1.63 (s, 6H, 2cH2)7 1.27 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 1.26 (t, J=6.8 Hz, 3H, CH3).

Preparation of compound 124b accordin~ to Scheme VI
(2E,4E)-3-Methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)he~a-2,4-dienoic acid (structure 22, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, Rg, Rg, and Rlo are hydrogen; R15 is hydroxy; X, Y, and Z are carbon; m = n =
1) Compound 124a was subjected to hydrolysis using the standard conditions of Example 2 to obtain the title acid 124b: Rf=0.48(50 % ether in hexane); mp 178-179~C;
lNMR(400 MHz, CDC13) ~ 7.07 (s, lH, ArH), 6.98 (s, lH, ArH). 6.23 (m, lH, olefnic), 6.15 (d, J=15.6 Hz, lH, olefinic), 5.72 (s, lH, olefinic), 2.86 (m, lH), 2.70 (brt, 2H, CH2, benzylic), 2.60 (m, lx allylic), 2.42 (m, lX allylic), 2.30 (s, 3H, CH3), 1.80 (m, 2X
CH2, methylene), 1.68 (m, 2H, CH2, methylene), 1.64 (s, 4H, 2CH2), 1.25 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).

Preparation of compound 125a according to Scheme VI
Ethyl (2E,4E)-3-methyl-6-(1,2,3,5,6,7,8-heptahydro-5,5,8,8-tetramethyl-cyclopenta[blnapthalen-l-yl)he~a-2,4-dienoate (stiucture 22, where Rl, R2, R3, R4, and Rlg are methyl, R5, R6, R7, Rg, Rg, Rlo are hydrogen, R15 is ethoxy, X, Y, Z are carbon, m = 1, and n = 0).
The title compound was prepared in a manner similar to that of compound 124a except that 2-[(E)-2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-cyclopenta[b]naphthalen-1-DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

ylidene]ethanitrile was employed as the starting material. The starting nitrile was prepared by condensation of 2,3,5,6,7,8 hexahydro-5,5,8,8-tetramethyl-cyclopenta[b]indan- 1 -one (US patent 2,815,382 (1957)) with the sodium anion of cyanomethylphosphonate. Title compound 125a had RfO.50 (10 % ether in hexane); lH NMR(400 MHz, CDC13) ~ 7.15 (s, lH, ArH), 7.12 (s, lH, ArH), 6.20 (m, lH, olefinic), 6.15 (d, J=15.7 HZ, lH, olefinic), 5.69 (s, lH, olefinic), 4.14 (q, 2H, OCH2), 3.15 (m, lH, CH), 2.85 (m, lH, benzylic), 2.75 (m, lH, benzylic), 2.65 (m, lH, allylic), 2.32 (m, lH, allylic), 2.27 (s, 3H, CH3), 2.20 (m, lH, methylene), 1.69 (m, lH, methylene), 1.65 (s, 4H, 2cH2)~ 1.26 (s, 6H, 2CH3), 1.24 (m, 9H, 3CH3).
10' Preparation of compound 125b accordin~ to Scheme VI
(2E,4E)-3-Methyl-6-1,2,3,5,6,7,8-heptahydro-5,5,8,8-tetramethyl-cyclopentalblnaphthalen-1-yl]he~a-2,4-dienoic acid (structure 22, where Rl, R2, R3, R4, and Rlg are methyl; R5, R6, R7, R8, Rg, and Rlo are hydrogen; Rls is hydroxy; ~, Y, and Z are carbon; m = 1, and n = O).
The title compound was prepared by hydrolysis of compound 125a using the standard condition of Example 2. Compound 125b had RfO.48(50 % ether in hexane);
mp 169-170~C; lHNMR(400 MHz, CDC13) ~ 7.16 (s, lH, ArH), 7.12 (s, lH, ArH), 6.24 (m, lH, olefinic), 6.18 (d, J=15.7 Hz, lX olefinic), 5.72 (s, lH, olefinic), 3.18 (m, lH, methine), 2.85 (m, lX benzylic), 2.78 (m, lH, benzylic), 2.65 (m, lH, allylic), 2.33 (m, lH, allylic), 2.29 (s, 3H, CH3), 2.17 (m, lH, methylene), 1.70 (m, lH, methylene), 1.65 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

EX~MPLE 41 Preparation of compound 126a accordin~ to Scheme VI
Ethyl (2E,4E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]he~a-2,4-dienoate (structure 22 where R1, R2, R3, R4 and 5 Rlg are methyl; R5, R6, R7, R8, Rg, and Rlo, are hydrogen; Rls is ethoxy; X, Y and Z
are carbon; m=l and n =2) To 11.0 g of diethyl cyanomethylphosphonate in 16 mL of dry THF was added 1.97 g of NaH to 25~C. The solution was stirred for 50 minutes, followed by addition of 4 g of 1-benzosuberone (Aldrich) in 5 rnL of dry THF. The reaction was warmed to 80~C
io for 12-16 h, cooled to room temperature and poured into saturated NH4CI solution. The products were extracted with EtOAc, washed with H2O and brine, dried over MgSO4,filtered and concentrated. The crude product was purified by chromatography (SiO2, 10 % EtOAc-hexanes) to give 4.1 g of (E)-2-[2-cyanomethenyl]benzosubarane: lH-NMR
(400 MHz, CDC13) o 7.12-7.32 (m, 4H, ArH), 5.31 (s, lH, olefinic), 2.75-2.78 (m, 4H, 2CH2), 1.90 (m, 2H, CH2), 1.80 (m, 2H, CH2 ).
To 2.1 g of (E)-2-[2-cyanomethenyl]benzosubarane in 20 mL of CH2C12 and 3.15 g of dichlorodimethylhexane at 25~ was added 3.06 g of ~ minllm trichloride. Themixture was stirred for 10 minutes, poured into H2O, and the product was extracted with 20% EtOAc-hexanes. The organic layer was washed with H2O and brine, dried over 20 MgS04, filtered and concentrated. Purification by chromatography (sio2~ hexanes) gave 1.8 g o~pure 2-[1,1,4,4-tetramethyl-1,2,3,4,7,8,9,10-octahydro-6H-naphthocycloheptan-10-yl]cyanomethylene: lH-NMR (400 ~Iz, CDC13) ~ 7.02 (s, lH, ArH), 7.01 (s, lH, ArH), 5:30 (s, lH, CH), 2.78 (t, J=12 Hz, 2H, CH2), 2.70 (t, J=12 Hz, 2H, CH2), 1.85 (m, 2H, CH2), 1.75 (m, 2H, CH2), 1.60 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.23 (s, 6H, 25 2CH3).
To 614 mg (2.10 mmol) ofthe above nitrile in CH2C12 (8 ml) at -78~C was added 1.68 mL (1.5 rnolar solution) of DIBAL. The mixture was stirred for 20 minutes at -78~C, then poured onto potassium-sodium tartrate solution, acidified with lN HCI, and the product extracted with ether. The ether layer was washed with H2O, brine, dried over DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

.
MgSO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography (5% EtOAc-hexanes) to give 412 mg of [1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]ethenal: lH-NMR (400 MHz, CDC13)~ 10.12 (d, J=12 Hz, lH, CHO), 7.12 (s, lH, ArH), 7.00 (s, lH, ArH), 6.10 (d, J=12 Hz, lH, olefinic), 2.92 (t, J=16 Hz, 2H, CH2)7 2.72 (t, J=16 Hz, 2H, CH2)7 1.87 (m, 2H, CH2), 1.80 (m, 2H, CH2), 1.68 (s, 4H, 2cH2)~ 1.27 (s, 6X 2CH3), 1.23 (s, 6H, 2CH3).
To 150 mg of aldehyde in EtOAc (3 ml) was added 15 mg of 10% Pd/C, and the mixture was stirred under one atmosphere of H2 gas for 2 hours, then filtered through a silica gel plug, and concentrated to give 140 mg of(l,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl)ethanal: Rf- 0.4 (10% EtOAc-hexanes); lH-N~ (400 M:Hz, CDC13) ~ 9.80 (s, lH, CHO), 6.95 (s, lH, ArH), 6.90 (s, lH, ArH), 3.70 (m, 2H, CH2), 3.50 (m, lH, CH), 3.00 (m, 2H, CH2), 2.6-2.8 (m, 2H, CH2), 1.80 (m, 4H, 2CH2), 1.60 (s, 4H, 2CH2), 1.32 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3).
To 372 mg of triethyl 3-methyl-4-phosphonocrotonate in 14 mL of dry 2:1 anhydrous THF-DMPU at -78~C was added 0.57 mL of a 2.5 M nBuLi solution in THF.
The reaction was stirred for 10 minlltes at -78~C, followed by addition of 140 mg ofthe above (1,1,4,4-tetramethyl-1,2,3,4,7,8,9,10-octahydro-6H-naphthocycloheptene-10-yl)ethanal in 3 rnL of dry THF. The reaction was stirred for an additional 10 minutes at -78~C, then warmed to room temperature. The reaction was poured into saturated NH4CI
and the product extracted with ether. The ether layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by preparative TLC (sio2~ 5% EtOAc-hexanes) to give 140 mg of the title ester 126a:RfO.6, (5% EtOAc-hexanes); lH-NMR (400 MHz, CDC13) o 6.99 (s, 2H, ArH), 6.13 (m, 2H, olefinic), 5.65 (s, lH, olefinic), 4.12 (m, 2H, -OCH2CH3), 2.91 (m, 2H, CH2), 2.81 (t, J=16 Hz, 2H, CH2), 2.70 (m, lH, CH), 2.56 (m, 2H, CH2), 1.68 (s, 4H, 2CH2), 1.20-1.30 (m, 15H, OCH2CH3 + 4CH3). A smaller amount (40 mg) ofthe correspondingZ,E-isomer was obtained as well.

DOCKET NO. . CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 126b accordin~ to Scheme VI
(2E,4E)-3-Methyl-6-[1,1,4,4-tetramethyl-1,2,3,4,7,8,9,10-octahydro-61EI-naphthocycloheptan-10-yllhexa-2,4-dienoic acid. (structure 22, where Rl, R2, R3, R4 -and R1g are methyl; R5, R6, R7, R8, Rg, and Rlo, are hydrogen; R15 is hydroxy; X, Y
and Z are carbon; m=l and n =2) Compound 126a (15 mg) was hydrolyzed by the standard method described in Example 2. The title compound was crystallized from EtOAc-hexanes to give 8 2 mg of 126b: RfO~3 (15% EtOAc-hexanes); lH-NMR (400 MHz, CDC13) ~ 7.00 (s, 2H, ArH), 6.19 (m, 2H, olefinic), 5.70 (s, lH, olefinic), 2.91 (m, 2H, CH), 2.80 (t, J=16 H~, 2H, CH2), 2.70 (m, lH, CH), 2.51 (m, 2H, CH2), 2.21 (s, 3H, CH3), 1.70 (m, 4H, 2CH2), 1.61 (s, 4H, 2CH2), 1.20-1.22 (m, 12H, 4CH3).

Preparation of compounds 127a and 127b accordin~ to Scheme VI
Ethyl (2Z,4E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-611-naphthocycloheptan-10-yl]hexa-2,4-dienoate. (structure 22, where Rl, R2, R3, R4 and Rlg are methyl; Rs, R6, R7, Rg, Rg, and Rlo are hydrogen; Rls is ethoxy; X, Y and Z are carbon; m=l and n=2) Prepared as a minor by-product from Example 41. Compound 127a had RfO.6;
(5% EtOAc-hexanes); lH-NM:R (400 MHz, CDC13) ~ 7.66 (d, J=16 Hz, lH, olefinic), 6.98 (s, 2H, ArH), 6.13 (m, lH, olefinic), 5.58 (s, lH, olefinic), 4.42 (m, 2H, OCH2CH3), 2.91 (m, 2H, CH), 2.81 (t, J=8 Hz, 2H, CH2), 2.74 (m, lH, CH), 2.61 (m, 2H, CH2), 2.00 (s, 3X CH3), 1.65 (m, 4H, 2CH2), 1.62 (s, 4H, 2CH2), 1.30-1.32 (m, 15H, OCH2CH3 +
4CH3).

(2Z,4E)-3-Methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6~I-naphthocycloheptan-10-yllhexa-2,4-dienoic acid. (structure 22, where Rl, R2, R3, R4 and Rlg are methyl; Rs, R6, R7, R8, Rg, and Rlo, are hydrogen; Rls is hydroxy; X, Y
and Z are carbon; m=1 and n =2) DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

The title compound was prepared from compound 127a by the hydrolysis method described in Example 2. Compound 127b had Rf~0.3 (15% EtOAc-hexanes); lH-NMR
(400 MHz, CDCl3) o 7.66 (d, J=16 Hz, lH, olefinic), 6.99 (s, 2H, ArH), 6.25 (m, lH, olefinic), 5.50 (s, lH, olefinic), 2.91 (m, 2H, CH2), 2.80 (m, 2H, CH2), 2.70 (m, lH, CH), 2.55 (m, 2H, CH2), 2.00 (s, 3H, CH3), 1.63 (m, 4H, 2cH2)~ 1.60 (s, 4H, CH2), 1.20-1.22 (m, 12H, CH3).

Preparation of compound 128b accordin~ to Schemes I and VI
(2E,4E)-3-Methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-2,2-dimethyl-pyran-4-yl]hexa-2,4-dienoic acid (structure 22, where Rl, R2, R3, R4, R7, Rg, and R1g are methyl; Rs, R6, Rg, Rlo are hydrogen; R15 is hydroxy; X and Y are carbon; Z is oxygen; m=n= 1).
[(E)-3,4,5,6,7,8-Hexahydro-2,2,5,5,8,8-hexamethylnaphtho(2,3-b)-1,2-pyran-4-ylidene]ethanitrile (400mg, 1.30 mmol, from Example 8) was converted to the corresponding aldehyde by means of the procedure described in Example 1. Flash chromatography (10% EtOAc/hexane) gave [(E)-3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethylnaphtho(2,3-b)-1,2-pyran-4-ylidene]acetaldehyde as a light yellow solid (220 mg, 0.70 mmol, 54%): lH NMR (400 ~Iz, CDCl3) ~ 10.1 (d, lH~, 7.53 (s, lH), 6.8 (s, lH), 6.60 (d, lH), 3.05 (s, 2H), 1.65 (s, 4H), 1.40 (s, 6H), 1.27 (s, 6H), 1.25 (s, 6H).
The above aldehyde (220 mg, 0.70 mmol) was hydrogenated using a procedure similar to that described in Example 41. TLC (20% EtOAc/hexane, cerium molybdate) indicated two products. Filtration and concentration gave a light yellow oil (140mg), which was purified by flash chromatography (20% EtOAc/hexane) to give [3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethylnaphtho(2,3-b)-1,2-pyran-4-yl]acetaldehyde as a clear oil which solidified on standing (39mg, 0.12 mmol, 18% yield): RfO.43 (20%
EtOAc/hexane); lH NMR (400 MHz, CDC13) ~ 9.9 (t, lH), 7.00 (s, lH), 6.7 (s, lH), 3.45 (m, lH), 3.05 (dd, lH), 2.70 (dd, lH), 2.00 (dd, lH), 1.65 (s, 4H), 1.60 (dd, lH), 1.31 (s, 6H), 1.26 (s, 6H), 1.24 (s, 6H).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Using the procedure described in Example 1, the above saturated aldehyde (39 mg,0.124 mmol) was coupled with diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate A total of 1.5 equivalents of phosphonate and sodium hydride were used in place of the original conditions. ~queous work up, followed by flash chromato~raphy (20%
EtOAc/hexane) afforded a mixture of ethyl (2E~4E)- and (2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-2,2-dimethylpyran-4-yl]hexa-2,4-dienoate as a clear oil (38mg, 0.089 mmol, 73% yield.). 1H NMR indicated a 2: 1 ratio of isomers favoring the trans product. These could not be separated by chromatography and were used as a crude mixture in the subsequent reaction: lH NMR (400 MHz, CDCl3) o 7.79 (d, lH), 7.15 (s, 2H), 6.7 (s, 2H), 6.20 (m, lH), 6.15 (m, 2X), 5.7 (d, lEI), 5.6 (d, lH), 4.10(m,4H),2.95(m,2H),2.90(m,2H),2.50(m, lH),2.40(m, lH),2.10(s,3H),2.00 (s, 3H), 1.82 (m, 2H), 1.62 (s, 8H), 1.60 (dd, 2H), 1.31 (t, 6H), 1.29 (s, 12H ), 1.26 (s, 12H), 1.24 (s, 12H).
The above mixture of esters (38 mg, 0.089 mmol) was hydrolyzed according to the standard procedure described in Example 2. A mixture of (2E,4E)- and (2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl (2,3-b )2,2-dimethylpyran-4-yl]hexa-2,4-dienoic acid was isolated as a light yellow solid (34 mg, 0.86 mmol, 96%): lH NMR
indicated a 2: 1 ratio of isomers favoring the lrans product. A 5 mg sample of the crude material was purified by HPLC (MeOH / 10 mM ammonium acetate) to give the title acid - 20 (128a) as an oily yellow solid (2.4 mg): lH NMR (400 MHz, CDC13) o 7.15 (s, lH), 6.7 (s, lH),6.22(m,2H),5.75(s, lH),2.90(m,2H),2.40(m, lH),2.30(s,3H~, 1.82(m, lH
), 1.65 (s, 4H), 1.60 (dd, lH), 1.29 (s, 6H), 1.26 (s, 6H), 1.24 (s, 6H).

Preparation of compound 129b accordin~ to Schemes I and II
(2Z,4E)-3-Methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-2,2-dimethylpyran-4-yl]hexa-2,4-dienoic acid (structure 22, where Rl, R2, R3, R4, R7, Rg, and R1g are methyl; Rs, R6, Rg, Rlo are hydrogen; Rls is hydroxy; X and Y are carbon;
Z is oxygen; m = n= 1).
A mixture of (2E,4E)- and (2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthyl(2,3-b)-2,2-dimethylpyran-4-yl]hexa-2,4-dienoic acid from Example DOCKET NO. CA 02209134 1997-06-27 O r6-0019A.WO

44 was purified by HPLC (MeOH / 10 mM ammonium acetate) to give the title acid as an oily yellow solid (2.2mg): lH NMR (400 MHz, CDC13) ~ 7.65 (d, lH), 7.15 (s, lH), 6.7 (s, lH), 6.20 (m, lH), 5.68(s, lH), 2.95 (m, 2H), 2.50 (m, lH), 2.00 (s, 3H), 1.82 (m, lH), 1.62 (s, 4H), 1.60 (dd, lH), 1.29 (s, 6H ), 1.26 (s, 6H), 1.24 (s, 6H).

Preparation of compound 130b according to Schemes IV and VI
(2E,4E)-3-Methyl-6- [5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-pyran-4-yl]-hexa-2,4-dienoic acid (structure 22, where Rl, R2, R3, R4, and Rlg are methyl; Rs, 10 R6, R7, R8, Rg, Rlo are hydrogen; Rls is hydroxy; X and Y are carbon; Z is oxygen; m =
n= 1).
To a stirred solution of diethyl cyanomethylphosphonate (13. lg, 74.3 mmol) in THF (50 ml) at -20~C under nitrogen was added dropwise, n-BuLi (29.5ml of a 2.5Msolution in hexanes). The resulting white viscous mixture was stirred for 1.5 h and treated with 4-chromanone (10.Og, 67.6 mmol, Aldrich) in THF (30 ml). The turbid, orangesolution was stirred in an ice water bath, then allowed to warm to room temperature over 45 min. TLC of the reaction mixture (20 % EtOAc/hexanes, cerium molybdate) indicated the formation oftwo product spots, RfO.23 and 0.36 respectively. The reaction mixture was quenched by dropwise addition of saturated ammonium chloride. Aqueous workup(and EtOAc extract), followed by filtration through a silica gel plug to remove excess phosphonate gave an isomeric mixture of 4-cyanomethylidenebenzopyrans (4:1 favoring the trans product) as a yellow oil (10. lg, 59.1 mmol, 87%): H NMR (400 MHz, CDC13) o 8.35 (dd, lH), 7.5 (d, 2H), 7.32 (m, 2H ), 7.0 (m, lH), 6.9 (m, 2H), 5.73 (s, lH), 5.17 (s, lH), 4.3 (m, 4H), 3.0 (dd, 2H), 2.75 (dd, 2H).
To a solution ofthe above nitriles (3.06g, 17.9 mmol) in EtOAc (25 ml) was added10% pall~ m on carbon (600 mg). This heterogeneous mixture was placed under an atmosphere of hydrogen and stirred at 25~C for 16 h. The reaction mixture was filtered and the solvent removed to give 4-cyanomethylbenzopyran as a rose colored oil (2.97 g, 17.2 mmol, 96%): H NMR (400 MHz, CDC13) o 7.16 (m, 2H), 6.9 (dd, lH), 6.83 (d, lH), 4.2 (m, 2H), 3.25 (m, lH), 2.82 (dd, lH), 2.6 (dd, lH), 2.3 (m, lH), 2.15 (m, lH).

DOCKET NO. CA 02209134 1997-06-27 016-00 1 9A.WO

To a solution of the above nitrile (2.9g, 16.8 mmol), 2,5-dichloro-2,5-dimethylhexane (3 . lg, 16. 8 mmol) in 1,2-dichloroethane (25 ml) at 25~C was added all~mimlm trichloride (3. lg, 16.8 mmol) in portions. The exothermic reaction was stirred for 2h, and the orange mixture was poured over ice. Aqueous work up ( EtOAc extraction), followed by recrystallization (MeOH /water) gave [5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)pyran-4-yl]cyanomethane, as white needles (3.0 g, 10.6 mmol, 63%): H NMR (400 l~Hz, CDC13) o 7.05 (s, lH,), 6.77 (s, lH ), 4.15 (m, 2H), 3.22(m, lH), 2.6 (dd, lH), '7.3 (dd, lH), 2.25 (m, lH), 1.95 (m, lH ), 1.65 (s, 4 H), 1.25 (s, 1 2H).
To a solution of the above tricyclic nitrile (1 .3g, 4.6 mmol) in THF (25 ml) at -78~C under nitrogen was added dropwise, DIBAL (3 ml of 1.0 M solution in CH2C12 ) The mixture was stirred for 30 min, warmed to 25~C, and stirred for 16 h. The reaction mixture was quenched by addition of saturated ammonium chloride, followed with lN HCI
and sodium potassium tartrate. Extractive work-up (EtOAc) gave [5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl (2,3-b)- pyran-4-yl]acetaldehyde as a light yellow solid (1.2 g, 4.2 mmol, 91.5%): H NMR (400 MHz, CDC13) o 9.90 ~t, lH), 7.00 (s, lH), 6.75 (s, lH), 4.15 (m, 2H), 3.45 (m, lH), 2.93 (dd, lH), 2.73 (dd, lH), 2.20 (m, lH), 1.80 (m, lH), 1.62 (s, 4H), 1.26 (s, 6H), 1.24 (s, 6H).
To a solution of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (475 mg, 1.80 mM) in THF (lOml ) at -78~C under nitrogen was added n-BuLi (0.75 ml of a 2.5M
solution in hexanes). The mixture was warmed to -20~C over 40 min, and the abovealdehyde (467 mg, 1.63 mmol) in THF (2 ml) was added in one portion. The reaction mixture was stirred at 0~C for 1 h, then quenched with saturated ammonium chloride.
Extractive work-up (EtOAc) gave ethyl (2E,4E)- and (2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl (2,3-b) pyran-4-yl]hexa-2,4-dienoate as a yellow oil.
Flash chromatography (20% EtOAc/hexane) gave the mixture of esters as a pale yellow oil (400 mg, 1.01 mmol, 62.9%): H NMR indicated the isomers in a 3 :1 ratio favoring the trans product. These could not be resolved by chromatography and were used as a mixture in subsequent reactions: H N~ (400 MHz, CDC13) o 7.6 (d, lH), 7.05(s, 2H), 6.72(s, lH), 6.25(m, 3H), 5.75(s, lH), 5.65 (s, lH), 4.15(m, 8H), 2.90(m, 2H), 2.71(m, 2H), 2.42 DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

(m, 2H ), 2.30 (s, 3H), 2.05 (m, 2~), 2.03 (s, 3H), 1.8 (m, 2H), 1.62 (s, 8H), 1.30 (t, 6H), 1.28 (s, 12H), 1.25 (s, 12H).
The mixture of esters (400 mg, 1.01 mmol) in ethanol (5 ml) was treated with sodium hydroxide (500 mg, 12.5 mmol) in a 60% ethanol/water solution (5 ml) and refluxed for 3 h.
The reaction mixture was cooled to 25~C, diluted with water, acidified with lN HCI and extracted (EtOAc) to give a rnixture of (2E,4E) and (2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro 5,5,8,8-tetramethylnaphthyl(2,3-b )pyran-4- yl]hexa-2,4-dienoic acid as a li~ht yellow solid (284 mg, 78 mmol, 78%). Recrystallization (MeOH/water) afforded 130b as an off-white solid (74 mg): TLC RfO.24 (20% EtOAc/Hexane); mp 195.6~C; H NMR (400 MHz, CDCl3) o 7.05 (s, lH), '6.72 (s, lH), 6.25 (m, 2H), 5.75 (d, lE~), 4.15 (dd, 2H), 2.90 (m, lH), 2.71 (m, lH ), 2.42 (m, lH), 2.30 (s, 3H), 2.05 (m, lH~, 1.8 (m, lH), 1.62 (s, 4 H), 1.26 (s, 6H), 1.24 (s, 6H).

Preparation of compound 131b accordin~ to Schemes IV and VI
(2Z,4E)-3-Methyl-6-15,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthyl (2,3-b ) pyran-4-yl]-hexa-2,4-dienoic acid (structure 22, where Rl, R2, R3, R4, and Rlg are methyl;
Rs, R6, R7, Rg, Rg, Rlo are hydrogen; Rls is hydroxy; X and Y are carbon; Z is oxygen;
n=m= 1).
Concentration of the second crop mother liquors from Example 46 gave a yellow oil. H NMR confirmed the structure as the corresponding (2Z,4E) acid. GC analysis of this material indicated 89% geometric purity with the rem~incler being the (2E, 4E) isomer:
Compound 131b had TLC Rf~0.23 (20% EtOAc/Hexane); HNMR (400 MHz, CDC13) o 760(d, lH),7.05(s, lH),6.72(s, lH),6.25(m, lH),5.65(m, lH),4.18(dd,2H),2.95 (m, lH ), 2.71 (m, lH), 2.50 (m, lH), 2.05 (m, lH), 2.03 (s, 3H), 1.8 (m, lH), 1.62 (s, 4 H), 1.26 (s, 6H), 1.24 (s, 6H).

Preparation of compounds 132b and 133b accordin~ to Scheme VII

-DOCKETNO. CA 02209l34 l997-06-27 016-0019A.WO

(+)-(2E,4E)-3-Methyl-6 (1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoic acid (structure 28, where Rl, R2, R3, R4 and R19 are methyl; Rs, R7, Rg, Rg and Rlo are hydrogen; Rls is hydroxy; X, Y and Z are carbon and m = n = 1).
The assigned absolute stereochemistry is arbitrary.
S Ester 18 (where Rl, R2, R3, and R4 are methyl; R5, R7, R8, Rg, and Rlo are hydrogen; X, Y and Z are carbon) (prepared in Example 34) (740 mg, 2.49 mmol) was dissolved in EtOAc (5.0 mL) and Pd/C 10% (20 mg) was added. The mixture was stirred under an atmosphere of hydrogen for 12 h. The mixture was filtered through a pad of celite and thoroughly rinsed with excess EtOAc. The solvent was evaporated to give 730 mg ~98% yield) ofthe ester: methyl (R,S)-2-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)acetate: lH NMR (400 MHz, CDC13) o 7.07 (s, lH, Ar), 6.99 (s, lX Ar), 3.72 (s, 3X OCH3), 3.30 (m, lH), 2.72 (m, 3H), 2.53 (dd, J=9.9, 8.2 Hz, lH), 1.89 (m, lH), 1.79 (m, 2H), 1.75 (m, lH), 1.75 (s, 4H), 1.24 (s, 12H).
The above ester (730 mg, 2.44 mmol) was dissolved in THF (5.0 mL) and LiOH
(2.0 mL of a 2.0 M aqueous solution) was added. The mixture was stirred at room temperature for 40 h, then acidified using 1 N HCL and extracted with EtO~c. Theorganic layer was dried over MgSO4, filtered, and evaporated to give the corresponding acid as a white solid, 648 mg (88% yield). The crude acid (648 mg, 2.16 mmol) was dissolved in dichloromethane (5.0 mL) and a drop of dimethylformamide was added.Oxalyl chloride (0.380 rnL, 4.32 mM) was added dropwise, followed by stirring at room temperature until the evolution of CO2 ceased (~ 2 h). The solvent was evaporated and the residue dried under high vacuum (~0.1 mmHg) to give the corresponding acid chloride (689 mg), (R,S)-2-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)-acetyl chloride.
A 50 mL round-bottom flask was flame-dried and charged with (S)-4-benzyl-2-oxazolidinone (576 mg, 3.25 mmol) and anhydrous THF (10 mL). The solution was cooled to -78~C and n-BuLi (2.1 mL, 1 55 M in hexanes) was added. The solution was stirred at -78~C for 30 min and a solution ofthe above acid chloride in THF (10 mL) was added slowly. Stirring was continued for 30 min, and the mixture was warmed to room temperature. A~er S min, the reaction mixture was cooled to -78~C, quenched with a saturated solution of ammonium chloride, and extracted with EtOAc (2 x 20 rnL). The DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

organic layer was washed with water (2 x 10 mL), brine (2 x 10 ml) and dried over MgSO4. Evaporation of the solvent gave a diastereomeric mixture of the corresponding amides (70% yield), which were chromatographically separated (hexanes: EtOAc=95:5).
The less polar amide had lH NMR (400 MHz, CDC13) ~ 7.36-7.22 (m, 5H, Ar), 7.18 (s, lH, Ar), 6.99 (s, lH, Ar), 4.71 (m, lH), 4.18 (m, 2H), 3.42 (m, lH), 3.35 (dd, J=14.9, 3.9 Hz, lH), 3.29 (s, lH), 3.27 (s, lH), 2.80 (d, J=12 Hz, lH), 2.80 ~d, J=12 Hz, lH), 2.75 (m, 2H), 1.90 (m, 2H), 1.76 (m, 2H), 1.65 (s, 4H), 1.26 (s, 6H), 1.24 (s, 6H); the more polar amide had lH N~ (400 MHz, CDC13) ~ 7.36-7.22 (m, 5 H, Ar), 7.00 (s, 1 H, Ar), 4.73 (m, 1 H), 4.20 (m, 2 H), 3.50 (m, 1 H), 3.34 (m, 2 H), 3.20 (m, 1 H), 2.75 (m, 3 H), 1.90 (m, 2 H), 1.75 (m, 2 H), 1.66 (s, 4 H), 1.28 (s, 6 H), 1.27 (s, 6 H).
A solution of the above more polar amide (190 mg, 4. 13 mmol) in THF (10.0 mL) was cooled to -78~C. LiAlH4 (0.425 mL of 1.0 M solution in THF) was added at -78~C, stirred for 30 min, then warmed to 0~C. The mixture was quenched with water (0.1 mL), NaOH (15%, 0.1 mL), and water (0.3 mL), then extracted with EtOAc (30 mL). The organic layer was dried over MgS04, and the solvent evaporated. The crude residue was purified by silica gel chromatography (hexanes: EtOAc=4: 1) to give 61 mg of the desired alcohol, (+)-2-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)ethan-1-ol (55% yield), [a]D +12.7 (c 0.59, CHC13).
The above alcohol (60 mg, 0.21 mmol) was dissolved in dichloromethane (5.0 mL) and Dess-Martin reagent (2 x 135 mg, 0.63 mmol) was added in two portions and stirred for 60 min. A saturated solution of sodium bicarbonate (3.0 mL) was added, followed by solid sodium thiosulfate. The mixture was stirred vigorously and extracted with dichloromethane. The organic layer was washed with water (2 x 5 mL), brine (2 x 5 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified over a short silica gel chromatography column to give 48 mg of the desired aldehyde, (+)-2-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)ethan-1-al (81% yield).
The above aldehyde was transformed to the title compound using a procedure similar to that described for the racemic material (Examples 37 and 38). Compound 132b had [a]D +16.2 (c 0.36, CHC13). The lHNMR spectrum was indistinglli.ch~ble from that ofthe racemate 124b.

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

(2E,4E)-3-Methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)he~a-2,4-dienoic acid (133b) (structure 29, where Rl, R2, R3, R4 and R1g are methyl;
- . -- R5, R7, R8, Rg and Rlo are hydrogen; Rls is hydroxy; X, Y, and Z are carbon; and m = n 5 = 1).
The title compound was prepared from the diastereomeric, less polar amide described above using the procedure for compound 132b. Compound 133b had ~a]D -16.4 (c 0.33, CHC13). lHNMR data is indistinguishable from racemic 124b.

Preparation of compound 134a according to Scheme VIII
Methyl (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)hex-2-enoate (structure 32, where Rl, R2, R3, R4 and Rlg are methyl; Rs, R6, R7, Rg, Rg, and Rlo are hydrogen; Rls is methoxy; X, Y, and Z are carbon; m= n=l) (1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)acetaldehyde, an intermediate for the preparation of compound 124a of Example 3 7, was condensed with the sodium anion of diethyl (2-oxopropyl)phosphonate to give (3E)- 1-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)pent-2-en-4-one: lH NMR (400 MHz, CDCl3) ~ 7.07 (s, lH, ArH), 7.00 (s, lH, ArH), 6.89 (m, lH, olefinic), 6.12 (d, J=15.9Hz, lH, olefinic), 2.94 (m, lH, benzylic), 2.72 (br t, 2H, CH2, benzylic), 2.68-2.47 (m, 2H, CH2, allylic), 2.26 (s, 3H, CH3), 1.82-1.62 (m, 4H, 2cH2)~ 1.66 (s, 4H, 2CH2), 1.26 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).
The above enone was subjected to hydrogenation using 10% Pd on C as a catalyst, followed by cond~n.~a~ion with trimethyl phosphonoacetate using NaH as a base to give methyl (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)hex-2-enoate: RfO.25 (hexane); lH NMR (400 MHz, CDC13) ~ 7.05 (s, lH, ArH), 6.97 (s,lH, ArH), 5.69 (s, lH, olefinic), 3.68 (s, 3H, OCH3), 2.69 (m, 3H, benzylic), 2.17 (s, 3H, CH3), 2.16 (m, 2H, allylic), 1.81 (m, 2H, CH2), 1.68 (s, 4H, 2CH2), 1.68-1.54 (m, 6H, 3CH2), 1.26 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 134b according to Scheme VIII
- (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)-hex-2-enoic acid (structure 32, where Rl, R2, R3, R4 and Rlg are methyl; R5, R6, R7, R8, Rg, and Rlo are hydrogen; R1s is hydroxy; X, Y, and Z are carbon; m= n=1) The title compound was prepared by hydrolysis of compound 134a using the standard hydrolysis conditions described in Example 2. Compound 134a had RfO.31 (50% ether in hexane); mp 190-192~C; lH NMR (400 MHz, CDC13) o 7.05 (s, lH, ArH), 6.98 (s, lH, ArH), 5.72 (s, lH, olefinic), 2.71 (m, 3H, benzylic), 2.20 (m, 2H, allylic), 2.18 (s, 3H, CH3), 1.82 (m, 2H, CH2)7 1.75-1.59 (m, 6H, 3CH2), 1.66 (s, 4H, 2CH2), 1.26 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3).

.. - EXAMPLE 51 Preparation of compound 135a accordin~ to Scheme IX
Ethyl (2E,4E)-3-methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-lEI-cyclopenta[a]naphthalen-3-ylidene]hexa-2,4-dienoate (structure 35, where R1, R2, R3, R4, and R1g are methyl; Rg and Rlo are hydrogen; Rls is ethoxy; X and Y are carbon; m = 1, andn=0).
The title compound was prepared from 2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-lH-cyclopenta[a]naphthalen-3-one [a by-product isolated from the preparation of 2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-cyclopenta[b]naphthalen-1-one in Example 3] in a manner similar to that described for compound 51a using the procedure described in Example 1. Compound 135a had 1H NMR (400 MHz, CDCl3) ~ 7.36 (d, J=8.27 Hz, lH, ArH), 7.26 (d, J=8.27 Hz, lH, ArH), 6.90 (dd, J=11.2, 15.1 Hz, lH, olefinic), 6.59 (d, J=11.2 Hz, lX olefinic), 6.31 (d, J=15.1 Hz, lH, olefinic), 5.78 (s, CH, olefinic), 4.18 (q, J=7.02 Hz, 2H, OCH2), 3.23 (br m, 2H, benzylic), 2.92 (br m, 2H, allylic), 2.37 (s, 3H, CH3), 1.69 (br s, 4H, 2cH2)~ 1.36 (s, 6H, 2CH3), 1.32 (s, 6H, 2CH3), 1.31 (t, J=7.0 Hz, 3H, CH3) DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 135b according to Scheme VIII
(2E,4E)-3-Methyl-6- [(E)-2,3,6,7,8,9-he~ahydro-6,6,9,9-tetramethyl-1 H-cyclopenta[a]naphthalen-3-ylidene]hexa-2,4-dienoic acid (structure 35, where Rl, R2, R3, R4, and Rlg are methyl; Rg and Rlo are hydrogen; R15 is hydroxy; X and Y arecarbon; m= 1, and n = 0).
The title compound was prepared from compound 135a using the standard hydrolysis condition described in Example 2. Acid 135b had mp 195-197~C; lH NMR
(400 MHz, CDC13) ~ 7.30 (d, J=8.2 Hz, lH, ArH), 7.21 (d, J=8.2 Hz, lH, ArH), 6.88 (dd, J=11.3, 15.1 Hz, lH, olefinic), 6.54 (d, J=11.3 Hz, lH, olefinic), 6.27 (d, J=15.1 Hz, lH, olefinic), 5.74 (s~ lH, olefinic), 3.17 (br m, 2H, CH2~ benzylic), 2.86 (m, 2H, CH2, allylic), 2.32 (s, 3H, CH3), 1.62 (br s, 4H, 2cH2)~ 1.28 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).

Preparation of compound 136a according to Scheme IX
Ethyl (2E,4E)-3-methyl-6-(2,3,6,7,8,9-he~ahydro-6,6,9,9-tetramethyl-lH-cyclopentala]naphthalen-3-yl]hexa-2,4-dienoate (structure 36, where Rl, R2, R3, R4, and Rlg are methyl; Rg and Rlo are hydrogen; Rls is ethoxy; X and Y are carbon; m = 1, and n= 0).
The title compound was prepared from (2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-lH-cyclopenta[a]naphthalen-3-ylidene)ethanitrile, which was prepared from the con~n~tion of 2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-lH-cyclopenta[a]naphthalen-3-one (Example 51) with cyanomethylphosphonate using NaH as a base in a manner similar to that described for compound 124a as detailed in Example 37. Compound 136a had 1H
NMR(400 MHz, CDC13) ~ 7.20 (d, J=8.0 Hz, lH, ArH), 7.03 (d, J=8.0 Hz, lH, ArH), 6.18 (m, 2X 2 x olefinic), 5.71 (s, lH, olefinic), 4.17 (q, J=7.6 Hz, 2X OCH2), 3.09 (m, 2H, CH2, benzylic), 2.97 (m, lH, benzylic), 2.67 (m, lH, allylic), 2.86 (s, 3X CH3), 2.19 (m, lH, allylic), 1.66 (m, 6H, 3cH2)~ 1.34 (s, 6H, 2CH3), 1.33 (s, 6H, 2CH3), 1.24 (t, J=7.0 Hz, 3H, CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 136b accordin~ to Scheme lX
(2E,4E)-3-Methyl-6-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-lH-cyclopenta[a]naphthalen-3-yl)hexa-2,4-dienoic acid (structure 36, where Rl, R2, R3, 5 R4, and Rlg are methyl; Rg and Rlo are hydrogen; R15 is hydroxy; X and Y are carbon;
m= l,andn=0) The title compound was prepared by hydrolysis of compound 136a using the standard hydrolysis conditions described in Example 2. Compound 136b had mp 208-210~C; 1H NMR (400 MHz, CDCl3) o 7.22 (d, J=8.0 Hz, lH, ArH), 7.03 (d, J=8.0 Hz, lH, ArH), 6.22 (m, 2H, 2-x olefinic), 5.75 (s, lH, olefinic), 3.10 (m, 2H, benzylic), 2.95 (m, lH, benzylic), 2.70 (m, lH, allylic), 2.30 (s, 3H, CH3), 2.20 (m, lH, allylic), 1.66 (m, 6H, 3CH2), 1.32 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3).

E~AMPLE 55 Preparation of compound 137a accordin~ to Scheme IX
Ethyl (2E,4E)-3-methyl-6-[(Z)-1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethyl-cyclope~ta[~naphthalen-4-ylidene]hexa-2,4-dienoate (structure 3~, where R1, R2, R3, R4, and Rlg are methyl; Rg and Rlo are hydrogen; Rls is ethoxy; X and Y are carbon; m =O,andn= 1) The title compound was prepared from 1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethyl-cyclopenta[flnaphthalen-4-one (isolated as a by-product for the preparation of 1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethyl-cyclopenta[b]naphthalen-5-one in Example 5) using the procedure described in example 51. Compound 137a had Rf=0.50 (15% ether in hexane); 1H NMR (400 MHz, CDCl3) ~: 7.25 (d, J=7.9 Hz, lH, ArH), 7.15 (dd, J=15.2, 11.4 Hz, lH, olefinic), 7.00 (d, J=7.9 Hz, lH, ArH), 6.30 (d, J=15.2 Hz, lH, olefinic), 6.14 (d, J=11.4 Hz, lH, olefinic), 5.76 (s, lH, olefinic), 4.16 (q, 2H, OCH2), 2.88 (t, J=6.4 Hz, 2H, benzylic), 2.51 (t, J=6.5 Hz, 2H, allylic), 2.29 (s, 3H, CH3), 1.91 (m, 4H, 2CH2), 1.42 (s, 6H, 2CH3), 1.29 (m, 9H, 3CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 137b accordin~ to Scheme IX
(2E,4E)-3-Methyl-6-[(Z)-1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethyl-cyclopenta[~naphthalen-4-ylidene]~exa-2,4-dienoic acid (structure 35, where Rl, R2, R3, R4, and R1g are methyl; Rg and R1o are hydrogen; R15 is hydroxy; X and Y arecarbon; m = 0, and n = 1) The title compound was prepared from compound 137a using the standard hydrolysis conditions described in Example 2. Compound 137b had Rf~0.45 (50% ether in hexane), mp 176-178~C; lH NMR (400 MHz, CDC13) o 7.24 (d, J=7.8 Hz, lH, ArH),7.19 (dd, J=15.2, 11.3 Hz, lH, ole~1nic), 7.00 ( d, J=7.9 Hz, lH, ArH), 6.33 (d, J=15.2 Hz, lH, olefinic), 6.16 (d, J=11.3 Hz, lH, olefinic), 5.79 (s, lH, olefinic), 2.88 (t, J=6.4 Hz, 2H, benzylic), 2.53 (t, J=6.4 Hz, 2H, allylic), 2.30 (s, 3H, CH3), 1.93 (m, 4H, 2CH2), 1.43 (s, 6H, 2CH3), 1.31 (m, 6H, 2CH3).
EXAMPLE ~7 Preparation of compound 138a accordin~ to Scheme X
Ethyl (2E,4E)-3-methyl-6-(7,7,10,10-tetramethyl-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-6]-azepinyl)hexa-2,4-dienoate (structure 40, where Rl, R2, R3, R4, and R1g are methyl; R5, R6, R7, R8, Rg, and R1o are hydrogen; R15 is ethoxy; X, Y, and Z are carbon; m = n = 1).
t 20 To a solution of 3,4,5,6,7,8-hexahydro-6,6,9,9-tetramethyl-2H-anthracen-1-one (256 mg, 1 mmol, from Example 1) in EtOH (10 ml) and pyridine (3 drops) was added H2NOH-HCl(140 mg, 2 mrnol) at 25~C, and resulting mixture was heated at reflux for 5 h. The mixture was cooled to room temperature and the filtered through filter paper and the solid was washed with hexane (50 ml). The solid was dried under vacuum to give pure trans-(3,4,6,7,8-hexahydro-6,6,9,9-tetramethyl-2H-anthracene-1-yl)-oxime (219 mg, 84%): 1H NMR(400 MHz, CDCl3) o 7.85 (s, lH, ArH), 7.05 (s, lH, ArH), 2.76 (t, J=6. 1 Hz, 2H, benzylic), 2.69 (t, J=6.0 Hz, 2H, CH2), 1.85 (m, 2H, CH2), 1.65 (s, 4H, 2CH2), 1.32 (s, 6H, 2CH3), 1.30 (s, 6H, 2CH3).
The above oxime (271 mg, I mmol) in THF(10 ml) was treated with LiAlH4 (3 ml, 1 M, 3 mM) at room temperature, and the resulting mixture was heated at reflux (80~C) ~ = ~
DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

for 8 h. The reaction mixture was cooled to 0~C, quenched with sodium potassium tartrate (20 ml), extracted with EtOAc(100 ml), dried over MgS04 and concentrated under reduced pressure. The crude product was chromatographed (20% ether in hexane) to afford pure 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-(2,3)-naphthyl-[b]azepine (218 mg, 85%): lH NMR(400 MHz, CDC13) ~ 6.95 (s, lH, ArH), 6.62 (s, lH, ArH), 3.01 (t, J=6.2 Hz, 2H, benzylic), 2.69 (br m, 2H, CH2)~ 1.73 (m, 2H, CH2)~ 1.62 (m, 2H, CH2)~ 1.61 (s, 4H, 2CH2), 1.25 (s, 12H, 4CH3).
To a solution of the above azepine (257 mg, 1 mmol) in THF (5 ml) was added NaH (80 mg, 60 % in oil, 2 mmol) at 0~C, and the resulting mixture was stirred at 0~C for 30 min. To this solution was added ethyl (2E,4E)-3-methyl-6-bromohexa-2,4-dienoate (233 mg, 1 mmol) [prepared by NaBH4 reduction of ethyl (2E,4E)-(3-methyl-5-formyl)penta-2,4-dienoate in Example 14, followed by bromination using PBr3 in ether at 0~C to afford the necessary bromo compound] in THF (5 ml) at room temperature, and the resulting mixture was stirred for 8 h. Standard work-up procedure as described in Example 1, followed by chromatographic purification (10% ether in hexane) gave the title ester (294 mg, 72%): RfO.78(20 % ether in hexane); lH NMR(400 MHz, CDC13) o 6.97(s, lH, ArH), 6.75 (s, lH, ArH), 6.32 (d, J=15.8 Hz, lH, olefinic), 6.22 (dt, J=15.8, 5.6 Hz, lH, olefinic), 5.72 (s, lX olefinic), 4.15 (q, J=7.0 Hz, 2H, OCH2), 3.85 (br d, J=5.6 Hz, 2H, allylic), 2.86 (br t, 2H, NcH2)~ 2.73 (m, 2H, benzylic), 2.25 (s, 3X CH3), 1.66 (m, 4H, CH2), 1.61 (s, 4H, 2CH2), 1.58 (m, 2H, CH2), 1.25 (t, J=7.0 Hz, 3H, CH3), 1.21 (s, 6H, 2CH3), 1.20 (s, 6H, 2CH3).

Preparation of compound 138b accordin~ to Scheme X
(2E,4E)-3-Methyl-6-17,7,10,10-tetramethyl-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-6]azepinyl)he~a-2,4-dienoic acid (structure 42, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, Rg, Rg, and Rlo are hydrogen; R15 is hydroxy; X, Y, and Z are carbon; m = n = 1).
The title compound was prepared from compound 138a using the standard hydrolysis conditions described in Example 2. Compound 138b as an amorphous solid had DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Rf-0.33 (50 % ether in hexane); lH NMR (400 MHz, CDC13) ~ 6.99 (s, lH, ArH), 6.75 (s, lH, ArH), 6.36 (d, J=15.7 Hz, lX olefinic), 6.22 (dt, J=15.7, 5.6 Hz, lX olefinic), 5.78 (s, lH, olefinic), 3.89 (d, J=5.6 Hz, 2H, allylic), 2.88 (br t, 2H, NCH2), 2.73 (m, 2H, benzylic), 2.28 (s, 3H, CH3), 1.69 (m, 2X CH2)~ 1.63 (s, 4H, 2cH2)~ 1.59 (m, 2H, CH2), 1.23 (s, 6H, 2CH3), 1.'~2 (s, 6H, 2CH3).

Preparation of compound 139a accordin~ to Scheme X
Ethyl 3-methyl-6-(3,4,6,7,8,9-he~ahydro-6j6,9,9-tetramethyl-2~I-benzo[glquinolin-l-yl)he~a-2,4-dienoate (structure 40, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, R8, Rg, Rlo are hydrogen; R15 is ethoxy; X, Y, and Z are carbon; m = 1, and n = 0).
The title compound was prepared from 2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-cyclopenta~b]naphthalen-1-one [U.S. patent 2,815,382 (1957)] in a manner similar to that described for compound 138a of Example 57. Ester 139a had lH NMR(400 MHz, CDC13) ~ 6.88 (s, lH, ArH), 6.51 (s, lH, ArH), 6.29 (d, J=15.7 Hz, lX olefinic), 6.15 (dt, J=15.7, 5.6 Hz, lH, olefinic), 5.72 (s, lH, olefinic), 4.16 (q, J=7.0 Hz, 2H, OCH2), 4.00 (d, J=5.6 Hz, 2X allylic), 3.23 (br t, 2H, NcH2)7 2.73( br t, 2H, benzylic), 2.25 (s, 3H, CH3), 1.96 (m, 2H, CH2), 1.63( s, 4H, 2CH2), 1.26 (t, J=7.0 Hz, 3H, CH3), 1.24 (s, 6H, 2CH3), 1.23 (s, 6H, 2CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 139b accordin~ to Scheme X
(2E,4~)-3-Methyl-6-[3,4,6,7,8,9-he~ahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-~l)he~a-2,4-dienoic acid (structure 40, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, Rg, Rg, and Rlo are hydrogen; Rls is hydroxy; X, Y, and Z are carbon; m = 1, and n = 0).
The title compound was prepared from compound 139a using the standard hydrolysis conditions detailed in Example 2. Compound 139b had mp 211- 213~C; lHNMR (400 M:Hz, CDC13) ~ 6.88 (s, lH, ArH3, 6.44 (s, lH, ArH), 6.33 (d, J=15.7 Hz, lH, olefinic), 6.20 (dt, J=15.7, 5.6 Hz, lX olefinic), 5.75 (s, lH, olefinic), 3.98 (d, J=5.6 Hz, 2H, allylic), 3.23 (br t, 2H, NcH2)~ 2.74 (br t, 2H, benzylic), 2.27 (s, 3H, CH3), 1.98 (m, 2H, CH2), 1.63 (s, 4H, 2CH2), 1.24 (s, 6H, 2CH3), 1.23 (s, 6H, 2CH3).

Preparation of compound 140a according to Scheme X
Ethyl (2E,4E)-3-methyl-6-oxo-6-[5,6,7,8-tetrahydro-5,5,8,~-tetramethyl(2,3)naphthyllb]piperidin-1-yl]he~a-2,4-dienoate (structure 42, where Rl, R2, R3, R4, and Rlg are methyl; R5, R6, R7, Rg, Rg, and Rlo are hydrogen; Rls isethoxy; X, Y, and Z are carbon; m=l, and n=0) 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl(2,3)naphthyl[b]piperidine (from Example 57) was coupled with ethyl (2E,4Z)-3-methyl-5-carboxylic acid-penta-2,4-dienoate[prepared by Jone's oxidation of ethyl (2E,4E)-(3-methyl-5-formyl)-penta-2,4-dienoate of Example 4] in the presence of DCC and DMAP and CSA as catalyst in CH2C12 to ~ive the title ester: RfO.50 (50% ether in hexane); lH NMR (400 MHz, CDC13) ~ 7.35 (d, J=15.3 Hz, lH, olefinic), 7.08 (s, lH, ArH), 6.85 (br s, lH, ArH), 6.63 (d, J=15.3 Hz, lH, olefinic), 6.05 (s, lH, olefinic), 4.18 (q, 2H, OCH2), 3.85 (t, J=6.5 Hz, 2H, NCH2), 2.65 (t, J=6.5 Hz, 2H, benzylic), 2.17 (s, 3H, CH3), 1.95 (m, 2H, CH2)~ 1.65 (s, 4H, 2CH2), 1.25 (m, 9H, 3CH3), 1.21 (s, 6H, 2CH3) -DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 140b according to Scheme X
(2E,4E)-3-methyl-6-o~o-6-(6,6,9,9-tetramethyl-3,4,6,7,8,9-he~ahydro-2H-benzolg~quinolin-l-yl)he~a-2,4-dienoic acid (structure 41, where Rl, R2, R-3, R4, and 5 Rlg are methyl; R5, R6, R7, Rs, Rg, and Rlo are hydrogen; X, Y, and Z are carbon;
~ . - m=l, and n=O) . - The title compound was prepared from compound 140a using the standard ~ -' hydrolysis conditions described in Exarnple 2. Compound 140b had RfO.25 (in ether);
mp 225-227~C; lH NMR (400 ~EIz, CDC13) ~ 7.37 (d, J=15.3 Hz, lH, olefinic), 7.08 (s, lH, ArH), 6.87 (br s, lH, ArH), 6.67 (d, J=15.3 Hz, lH, olefinic), 6.08 (s, lH, olefinic), 3.86 (t, J=6.5 Hz, 2H, NH2)~ 2.68 (t, J=6.5 Hz, 2H, benzylic), 2.19 (s, 3H, CH3), 1.96 (m, 2H, CH2), 1.66 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.98 (s, 6H, 2CH3).

Preparation of compound 141a according to Scheme Xt Ethyl (2E,4E)-3-methyl-6-o~o-6-[(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl)-benzo[flindol-l-yl~he~a-2,4-dienoate (structure 47, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, Rg and Rlo are hydrogen; R15 is ethoxy; X is carbon; m=l, and n=O) 2,5-Dimethyl-2,5-dichlorohexane was coupled with oxindole in CH2C12 at 25~C in the presence of AIC13 to obtain 2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-lH-benz~ -2-oxo-indole, which was reduced with DIBAL in CH2C12 at reflux temperature to give 2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-lH-benz[f~-indole: lH NMR (400 MHz, CDC13) o 7.08 (s, lH, ArH), 6.61 (s, lH, ArH), 3.51 (t, J=8.0 Hz, 2H, N-CH2), 2.98 (t, J=8. lHz, 2H, benzylic), 1.64 (s, 4H, 2CH2), 1.24 (s, 6H, 2CH3), 1.23 (s, 4H, 2CH2).
The above indole was then coupled with ethyl (2E,4E)-3-methyl-5-carboxylic acid-pent-2,4-dienoate (Example 61) using DCC and DMAP as reagents and CSA as a catalyst in CH2C12 at -78~C to give the title ester: Rf~0.50 (50% ether in hexane); lH NMR (400 :MHz, CDC13) ~ 8.32 (s, lH, ArH), 7.44 (d, J=15.1 Hz, lH, olefinic), 7.15 (s, lH, ArH), 6.62 (d, J=15.1 Hz, lH, olefinic), 6.06 (s, lH, olefinic), 4.20 (m, CH2;ocH2)~ 3.19 (brt, DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

J=9.3 Hz, 2H, benzylic), 2.30 (s, 3H, CH3), 1.68 (s, 4H, 2CH2), l .31 (m, 9H, 3CH3), 1.26 (s, 6H, 2CH3).

5 Preparation of compound 141b accordin~ to Scheme ~
(2E,4E)-3-Methyl-6-o~o-6-[(2,3,5,6,7,8-he~ahydro-5,5,8,8-tetramethyl)benzo-[t~-indol-l-yl]hexa-2,4-dienoic acid (structure 46, where R1, R2, R3, R4, and R1g are methyl; Rg and R1o are hydrogen; X, and Y are carbon; and m=1) The title acid was prepared from compound 141a using the standard hydrolysis conditions described in Example 2. Compound 141b had RfO.15 (50% ether in hexane);
mp 226-228~C; lH NMR (400 MHz, CDC13) o 8.33 (s, lH, ArH), 7.47 (d, J=15.1 Hz, lH, olefinic), 7.16 (s, lH, ArH), 6.67 (d, J=15.1 Hz, lH, olefinic), 6.11 (s, lH, olefinic), 4.21 (t, J=8.1 Hz, 2X NcH2)7 3.20 (t, J=8.1Hz, 2X benzylic), 2.36 (s, 3H, CH3), 1.68 (s, 4H, 2CH2), 1.32 (s, 6H, 2CH3), 1.27 (s, 6X 2CH3).

Preparation of compound 142a accordin~; to Scheme XI
Ethyl (2E,4E)-3-methyl-6-(2,3,5,6,7,8-he~ahydro-5,5,8,8-tetramethylbenzo-l~-indol-l-yl]he~a-2,4-dienoate (structure 46, where R1, R2, R3, R4 and R1g are methyl; Rg and R1o are hydrogen; R1s is ethoxy; X and Y are carbon; and m=1) 2,3,5,6,7,8-Hexahydro-5,5,8,8-tetramethyl-lH-benz-[~-indole (prepared previouslyin Example 63) was coupled with (2E,4E)-3-methyl-6-bromo-hexa-2,4-dienoate (prepared previously in Example 57) using NaH as base and THF as solvent to give the titlecompound: RfO.80 (50% ether in hexanes); lH NMR (400 MHz, CDC13) o 7.05 (s, lH, ArH), 6.42 (s, lH, ArH), 6.41 (d, J=16.4 Hz, lX olefinic), 6.19 (m, lH, olefinic), 5.85 (s, lH, olefinic), 4.16 (q, 2H, OCH2), 3.80 (d, J=5.7 Hz, 2H, NCH2, allylic), 3.30 (t, J=8.0 Hz, 2H, NCH2), 2.91 (t, J=8.0 Hz, 2H, benzylic), 2.28 (s, 3H, CH3), 1.64 (s, 6H, 2CH3), 1.27 (m, 9H, 3CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

, .~

Preparation of compound 142b according to Scheme ~:
(2E,4E)-3-Methyl-6-(2,3,5,6,7,8-he~ahydro-5,~,8,8-tetramethylbenzo[flindol-1-yl]he~a-2,4-dienoic acid (structure 47, where Rl, R2, R3, R4, and Rlg are methyl; Rg and Rlo are hydrogen; R15 is hydroxy; X and Y are carbon; and m=l) The title compound was prepared from compound 142a using the standard hydrolysis conditions described in Example 2. Acid 142b had RfO.30 (50% ether in hexane); mp 170-171~C; lH NMR (400 MHz, CDC13) ~ 7.06 (s, lH, ArH), 6.41 (s, lH, ArH), 6.39 (d, H=16.2 Hz, lH, olefinic), 6.28 (m, lH, olefinic), 5.79 (s, lH, olefinic), 3.81 (d, J=5.7 Hz, 2H, N-CH2, allylic), 3.30 (t, J=8.1 Hz, 2H, NcE~2)~ 2.92 (t, J=8.1 Hz, 2H, benzylic), 2.30 (s, 3H, CH3), 1.64 (s, 4H, 2CH2), 1.23 (s, 12H, 4CH3).

Preparation of compound 143a according to Scheme XII
Ethyl (2E,4E)-3-methyl-6-(7,7,10,10-tetrahydro-5,5,8,8-tetramethyl)benzolf~quinolin-4-yl)he~a-2,4-dienoate (structure 50, where Rl, R2, R3, R4, and R1g are methyl; Rg and R1o are hydrogen; R1s is ethoxy; X and Y are carbon;
m=1, and n=O) 2,3,6,7,8,9-Hexahydro-6,6,9,9-tetramethyl-lH-cyclopenta[a~naphthalen-3-one '~ 20 (prepared previously in Example 51) was coupled with H2NOH-HCI to give the oxime which, without further purification, was subjected to LAH reduction to give 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl(1,2)-naphthyl-[b]-piperidine: lH NMR (400 MHz, CDC13) ~6.95(d,J=8.7Hz, 1XArH),6.32(d,J=8.7Hz, lH,ArH),3.25(t,J=6.3Hz,2H, NCH2), 2.90 (t, J=6.0 Hz, 2X benzylic), 1.87 (m, 2H, CH2), 1.61 (m, 4H, 2CH2), 1.40 (s, 6X 2CH3), 1.22 (s, 6X 2CH3).
The above piperidine was then converted to the title compound in a manner similar to that of compound 89a as described in Example 59. Compound 143a had RfO.75 (20%
ether in hexane); lH NMR (400 MHz, CDC13) o 7.05 (d, J=8.7 Hz, lH, ArH), 6.46 (d, J=8.7 Hz, lH, ArH), 6.24 (d, J=15.8 Hz, lH, olefinic), 6.13 (m, lH, olefinic), 5.73 (s, lH, olefinic), 4.15 (q, J=7.2 Hz, 2H, OCH2), 3.94 (d, J=4.8 Hz, 2H, N-CH2-allylic), 3.17 (t, DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

J=6.3 Hz, 2H, N-CH2), 2.90 (t, J=5.9 Hz, 2H, benzylic), 2.26 (s, 3H, CH3), 1.97 (m, 2H, CH2), 1.62 (m, 6H, 2CH3), 1.27 (t, J=7.2 Hz, 3H, CH3), 1.24 (s, 6H, 2CH3).

- 5 Preparation of compound 143b according to Scheme ~I
(2E,4E)-3-Methyl-6-(1,2,3,4,7,8,9,10-octahydro-7,7,10,10-tetramethylbenzolf~quinolin-4-yl)he~a-2,4-dienoic acid (structure ~0, where Rl, ~2, R3, R4, and R1g are methyl; Rg and Rlo are hydrogen; R15 is hydroxy; X and Y are carbon; m=l, and n=0) The title compoùnd was prepared from compound 143a using the standard hydrolysis conditions in Example 2. Compound 143b had Rf-0.50 (50% ether in hexane);
amorphous solid HRMS Calc. C26H33o2N 367.2511, found 367.2504; lH NMR (400 MHz, CDCl3) ~ 7.06 (d, J=8.7 Hz, lX ArH), 6.46 (d, J=8.7 Hz, lH, ArH), 6.28 (d, J=15.7 Hz, lH, olefinic), 6.22 (m, lX olefinic), 5.75 (s, lH, olefinic), 3.95 (d, J=4.7 Hz, 2H, N-CH2-allylic), 3.18 (t, J=6.2 Hz, 2H, N-cH2)~ 2.90 (t, J=6.0 Hz, 2H, benzylic), 2.27 (s, 3H, CH3), 1.90 (m, 2H, CH2), 1.61 (m, 4H, 2CH2), 1.40 (s, 6X 2CH3), 1.27 (s, 6H, 2CH3).

Preparation of compound 144b accordin~ to Scheme II
(2E, 4E)-3-Methyl-6-[(Z)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b-pyran-4-ylidene]hexa-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4 and R1g are methyl; Rs, R6, R7, Rg, Rg and Rlo are hydrogen; R15 is hydroxy; X and Y are carbon; Z
is oxygen; m=n=1).
The title compound was prepared in a manner similar to that of compounds 56a and 56b (Examples 10 and 11) except that 6,6,9,9-tetramethyl-6,7,8,9-tetrahydrobenzo[g~-chromene-4-one was used as the starting ketone (structure 1 in Scheme II). The synthesis of this interme~i~te ketone is detailed below.
A 200rnl round bottom flask was flame dried under nitrogen and charged with sodium metal (3.2g, 140 mmol). A solution of 3-aceto-5,6,7,8-tetrahydro-5,5,8,8-DOCKET NO. CA 02209134 1997-06-27 016-00 l9A.WO

tetramethyl-2-naphthol (15g, 61.0 rnmol, from Example 7) in ethyl formate (350ml) was added dropwise over 1 h. The resulting yellow solution was stirred at 35~C for 4 h. The mixture was cooled to 25~C solution, diluted with lN HCl (20ml) and extracted with ether.
The extracts were washed with water, brine, and dried over Mg~04. The extracts were concentrated under vacuum to give 2-hydroxy-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydrobenzo[g]chromen-4-one structure 1 where Rl, R2, R3, and R4 are methyl; Rs, R6, and R7 are hydrogen; R8 is hydroxy; ~ and Y are carbon; Z is oxygen; and m=n=l)]:
lH NMR (400 MHz, CDC13) o 7.85 (s, lH), 6.9 (s, lH), 5.85 (t, lH), 3.32 (br s, lH), 2.9 (dd, 2H), 1.67 (s, 4H), 1.27 (s, 12H).
To a solution of above benzochromen-4-one (19.6g, 71.5 mmol) in methanol (250ml) was added conc HCI (0.5ml) dropwise. The mixture was stirred at 60~C for 2.5 h.
TLC analysis indicated the reaction was complete. The mixture was cooled to 25~C and diluted with water (200ml). A light brown solid precipitate was collected by filtration and dissolved in ether, washed with water, brine and dried over sodium sulfate. Concentration under vacuum gave 6,6,9,9-tetramethyl-6,7,8,9-tetrahydrobenzo[g]chromen-4-one (13.3g, 52.0 mmol, 73%) as a light brown solid: mp 202.1~C; lH NMR (400 MHz, CDCl3) o
8.15 (s, lH), 7.8 (d, lH), 7.4 (s, lH), 6.25 (d, lH), 1.75 (s, 4H), 1.35 (s, 12H).
A solution of 6,6,9,9-tetramethyl-6,7,8,9-tetrahydrobenzo[g]chromen-4-one (4.4g,17.2 mmol) in 1:1 EtOAc/methanol (250ml) cont~ining 10% p~ m on carbon (l:lg, 7% by weight) was stirred at room temperature under an atmosphere of hydrogen (balloon) for 14 h. TLC analysis indicated complete reaction. The mixture was filtered and concentrated to give a yellow oil. The oil was passed through a small column of silica (10% EtOAc in hexane) and concentration to give 6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydrobenzo[g]chromen-4-one (4.2g, 16.3 mmol, 95%) as a light yellow solid: 1H
NMR (400 MHz, CDC13) o 7.85 (s, lH), 6.86 (s, lH), 4.46 (t, 2H), 2.75 (t, 2H), 1.65 (s, 4H), 1.25 (s, 12H).
The above hexahydrobenzo[g]chromen-4-one was transformed to the title compound as outlined in Scheme II and Examples 10 and 11. Compound 144b was obtained as a bright yellow solid: mp 228.5~C; RfO.26 (40% ether in hexane); lH NMR
~400 MHz, CDCl3) ~ 7.42 (dd, lH), 7.38 (s, lH), 6.8 (s, lH), 6.4 (d, lH), 6.07 (d, lH), DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

532(s, lH),4.32(t,2H),2.66(t,2H),2.35(s,3H), 1.68(s,4H), 1.28(s,6H), 1.26(s, 6H).

5 Preparation of compound 145b according to Scheme II
(2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethyl-21~-anthracen-l-ylidenelhe~a-2,4-dielloic acid (structure 7, where Rl, R2, R3, R4, R5, R6,and Rlg are - methyl; R7, Rg, Rg, and Rlo are hydrogen; Rls is hydroxy; X, Y, Z are carbon; m = n =
1) ~
The title compound was prepared in a manner similar to Example 10, except that 2,5,5,8,8-3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethyl-2H-anthracen-l-one was used as the starting tricyclic ketone which was prepared by the following sequence.
The tricyclic ketone, 2, 5, 5, 8, 8 -3, 4, 5, 6, 7, 8 -hexahydro-2, 5, 5, 8, 8 -pentamethyl-2H-anthracen-l-one (0.640 g, 2.50 mmol) in THF (5.00 mL) was added dropwise to a prepared solution of LDA (2.75 mmol, 1.1 eq) in THF at -78~C. The resulting blue-green solution was stirred at -78~C for 45 min. Iodomethane (0.707 g, 5.00 mmol, 0.311 mL) was added dropwise and the solution was stirred for lh at -78~C. The reaction solution was warmed to room temperature and became red in color. After stirring for 1.5h, the reaction solution was quenched with water and the aqueous layer extracted with EtOAc (3 20 x 10 mL). The combined organic extracts were washed with H20 and brine, dried(MgSO4), filtered, and concentrated to give the crude methylated tricycle (0.687 g).
Purification by radial chromatography (20:1 = Hex:THF) gave the dimethylated tricycle (0.090 g, 13%) as a white solid: lH NMR (400 MHz, CDCl3) ~ 8.02 (s, lH, Ar-H)7 7.13 (s, lH, Ar-H), 2.92 (t, 2H, 2CH), 1.95 (t, 2H, 2CH), 1.67 (s, 4H, CH2), 1.30 (s, 6H, 2CH3), 1.29 (s, 6H, 2CH3), 1.21 (s, 6H, 2CH3).
Procedures similar to those in Examples 10 and 11 afforded the compound 145b as a yellow solid. lH N~ (400 MHz, CDCl3) ~ 7.22 (s, lH, Ar-H), 7.18 (dd, J = 11.0, 15.2 Hz, lH, olefinic), 7.07 (s, lH, Ar-H), 6.41 (d, J= 15.2 Hz, lH, olefinic), 6.28 (d, J= 11.0 Hz, lH, olefinic), 5.80 (s, lH, olefinic), 2.76 (t, J = 6.6 Hz, 2H, CH2), 2.28 (s, 3H, CH3), DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

1.69 (s, 4H, CH2), 1.68 (t, J = 6.6 Hz, 2H, CH2), 1.29 (s, 12H, 4CH3), 1.16 (s, 6H, 2CH3).

EXA~PLE 71 5 Preparation of compound 146a accordin~ to Scheme II
Ethyl (2E,~E)-3-methyl-6-~(Z)-N-acetyl-3,4,5,6,7,8-hexahydro-10-amino-5,5,8,8-tetramethyl-2~:-anthracen-1-ylidene]he~a-2,4-dienoate (structure 7, where Rl, R2, R3, R4, and Rlg are methyl; R5, R6, R7, R8 and R1o are hydrogen; Rg is N-acetylamino; Rls is ethoxy; ~, Y, Z are carbon; m = n = 1) The title compound was prepared in a manner similar to Example 10, except that 10-nitro-1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-one (from Example 8) was used as the starting tricyclic ketone and generation of the intermediate cis-olefinic ester was accomplished with catalytic TsOH in EtOH; the 10-nitrotricyclic cis-allylic alcohol was prepared from the ester as described in Example 10: lH N~ (400 MHz, CDCl3) o 7.32 (s, lH, aromatic), 5.71 (t, J= 6.8 Hz, lH, olefinic), 4.36 (collapsed dd, 2H, allylic), 2.59 (apparent t, J = 6.6 Hz, 2H, CH2)~ 2.42 (m, 2H, CH2), 1.91 (m, 2H, CH2), 1.73 (m, 2H, CH2), 1.68 (m, 2H, CH2), 1.57 (s, 6H, 2CH3), 1.31 (s, 6H, 2CH3).
The intermediate 10-nitrotricyclic cis-allylic alcohol (250 mg, 0.76 mmol) in EtOH
(4.5 mL) and water (1.0 mL) was treated with calcium chloride (54 mg) in water (0.1 mL) and zinc dust (1.63 g) at ambient temperature and the mixture was heated at reflux for 2 h.
The hot mixture was filtered through a pad of celite and the filter pad was rinsed with hot EtOH (50 mL). The solution was concentrated in vacuo, diluted with water and extracted with EtOAc. The EtOAc layer was washed with water, saturated aqueous NaHCO3, water, and brine. The solution was dried (Na2SO4), filtered, and concentrated to give 10-aminotricyclic cis-allylic alcohol, 225mg (99%) as a yellow oil: lH N~ (400 MHz,CDCl3) o 6.66 (s, lH, aromatic), 5.56 (t, J= 6.5 Hz, lH, olefinic), 4.46 (d, J = 6.5 Hz, 2H, allylic), 3.82 (broad s, 2H, NH2), 2.51 (m, 2H, CH2), 2.38 (m, 2H, CH2), 2.04 (m, 2H, CH2), 1.73 (m, 2H, CH2), 1.64 (m, 2H, CH2), 1.45 (s, 6H, 2CH3), 1.29 (s, 6H,2CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

The amino alcohol (200 mg, 0.67 mmol), in methylene chloride (1 mL) and lutidine(0.2 mL) was treated with t-butyldimethylsilyl triflate (195 mg, 0.74 mmol) at ambient temperature and the solution was allowed to stir for 8 h. The reaction was quenched with saturated aqueous NH4CI and diluted with EtOAc. The EtOAc layer was washed with 5 water, saturated aqueous NaHCO3, water, and brine. The solution was dried (Na2S04), filtered, and concentrated to give the crude product. The product was purified by silica gel radial chromatography (20: 1 = Hex: EtOAc) to give the 10-amino silyl protected cis-allylic alcohol 128 mg (46%) as a colorless oil: lH NMR (400 MHz, CDC13) ~ 6.71 (s, lH, aromatic), 5.57 (t, J = 6.2 Hz, lH, olefinic), 4.53 (d, J = 6.2 Hz, 2H, allylic), 3.84 (broad s, 2H, NH2), 2.54 (apparent t, J = 6.7 Hz, 2H, CH2)~ 2.42 (m, 2H, CH2), 2.06 (m, 2H, CH2), 1.77 (m, 2H, CH2), 1.68 (m, 2H, CH2)~ 1.49 (s, 6H, 2CH3), 1.34 (s, 6H,2CH3), 0.96 (s, 9H, 3CH3), 0.12 (s, 6H, 2CH3).
The 10-amino silyl protected cis-allylic alcohol (95 mg, 0.23 mmol), in methylene chloride (2 mL) and pyridine (0.3 mL) was treated with a catalytic amount of DMAP and acetic anhydride (1.15 mmol) and the solution was heated at reflux for 12 h. The reaction was quenched with the adition of water and diluted with EtOAc. The EtOAc layer was washed with water, saturated aqueous NaHCO3, water, and brine. The solution was dried (Na2SO4), filtered, and concentrated to give the crude product. The product was purified by silica gel radial chromatography (1: 1 = Hex: Et2O) to give the N-acyl-10-amino silyl 20 protected cis-allylic alcohol 67 mg (70%) as a colorless oil. The protected cis-allylic alcohol (0.16 mmol) was dissolved in THF (0.5 mL) and treated with tetrabutylammonium fluoride (1 M, 2.1 eq) at ambient temperature and the solution was allowed to stir for 8 h.
The reaction was quenched with water and diluted with EtOAc. The EtOAc layer waswashed with water, saturated aqueous NaHCO3, water, and brine. The solution was dried 25 (Na2SO4), filtered, and concentrated to give the crude product. The product was crystallized (CH2C12 / hexanes) to give the N-acyl- 10-amino cis-allylic alcohol 44 mg (89%) as a yellow solid. The alcohol (0.13 mmol) was oxidized with MnO2 (20 mg, 0.23 mmol) in methylene chloride (0.5 mL) at ambient temperature for 18 hours. The reaction was quenched with the addition of water and diluted with EtOAc. The EtOAc layer was 30 washed with water, saturated aqueous NaHCO3, water, and brine. The solution was dried DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

(Na2S04), filtered, and concentrated to give the N-acyl- 1 0-amino cis-unsaturated aldehyde 43 mg (99%) as a yellow oil: lH NMR (400 MHz, CDC13) o 9.78 (d, J = 7.9 Hz, lH, CHO), 7.02 (s, lH, aromatic), 6.02 (d, J = 7.9 Hz, lH, olefinic), 2.69 (m, 2H, CH2), 2.58 (m, 2H, CH2), 2.23 (s, 3H, CH3), 1.92 (m, 2H, CH2)~ 1.69 (m, 4H, 2CH2), 1.40 (m, 6H, 2CH3), 1.27 (s, 6H, 2CH3).
Using the procedure described in Example 1, the above aldehyde was transformed into the title compound 146a, which was obtained as a yellow oil: lH NMR (400 MHz, CDC13) o 7.34 (s, lH, aromatic), 7.13 (dd, J-15.1, 11.1 Hz, lH, olefinic), 6.43 (d, J=15.1 Hz, lH, olefinic), 6.15 (d, J=11.1 Hz, lH, olefinic), 5.80 (broad s, lH, olefinic), 4.14 (q, J=7.0 Hz, 2H, -OCH2); 2.64 (m, 2H, CH2), 2.48 (m, 2H, CH2), 2.29 (s, 3H, CH3), 2.22 (s, 3H, CH3 allylic), 1.94 (m, 2H, CH2)~ 1.87 (m, 2H, CH2)~ 1.69 (m, 2H, CH2), 1.30 (s, 12H, 4CH3); 1.28 (t, J=7.0 Hz, 3H, CH3 ethyl).

Preparation of compound 146b according to Scheme II
(2E,4E)-3-methyl-6-1(Z)-N-acetyl-3,4,5,6,7,8-hexahydro-10-amino-5,5,8,8-tetramethyl-2E~-anthracen-l-ylidenelhexa-2,4-dienoic acid (structure 7, where Rl, 1~2, R3, R4, and R1g are methyl; R5, R6, R7, R8 and Rlo are hydrogen; Rg is N-acetylamino;
R1s is hydroxy; X, Y, Z are carbon; m = n = 1) Compound 143a was hydrolyzed using the procedure of Example 2, to give the title compound 143b 20.5 mg (30%) as a yellow film: 1H NMR (400 MHz, CDC13) o 7.36 (s, lH, aromatic), 7.16 (dd, J=15.1, 11.1 Hz, lH, olefinic), 6.73 (s, lH, NH), 6.36 (d, J=15.1 Hz, lH, olefinic), 6.18 (d, J=ll.1 Hz, lH, olefinic), 5.81 (broad s, olefinic), 2.64 (m, 2H, CH2), 2.48 (m, 2H, CH2)~ 2.29 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.94 (m, 2H, CH2), 1.87 (m, 2X CH2), 1.69 ~m, 2H, CH2), 1.30 (s, 12X 4CH3).

Preparation of compound 147b accordin~ to Scheme ~II

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

~9 (2E,4E)-3-methyl-6-[(E)l-ethyl-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydro- lH-benzolg]
quinolin-4-ylidenelhe~a-2,4-dienoic acid (structure 7, where Rl, R2, R3, R4, and R1g are methyl; R5, R6, R7, R8, Rg and Rlo are hydrogen; R15 is hydroxy; X, Y are carbon, Z is N-ethyl; m= n = 1) The title compound was prepared in a manner similar to Example 1 except that 1-ethyl-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydro-lH-benzo[g] quinolin-4-one was used as the starting tricyclic ketone, which was prepared by the following sequence.
Nitric acid (15.3g, 218mmol ) was added dropwise to 1,2,3,4-tetrahydro-1,1,4,4 tetramethylnaphthalene (13.7g, 72.9 mmol ) at O ~C. Following this addition, the reaction mixture was allowed to warm to 25 ~C over 2 hours. The reaction mixture was poured onto ice (200 g), neutralized by addition of sodium carbonate and extracted with ethyl acetate.
Removal of solvent under reduced pressure yielded a light brown oil which crystallized upon st~nding (15.7g, 68.0 mmol, 93% ): lH NMR (400 MHz, CDC13) o 8.17 (d, lH, ArH), 7.95 (dd, lH, ArH), 7.45 (d, lH, ArH), 1.75 (br s, 4H, CH2)~ 1.32 (s, 6H, CH3), 1.28(s, 6H, CH3).
A solution of 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydronaphthalene (15.7g, 68.0 mmol) and 10% palladium on carbon (1.57g ) in ethyl acetate (19Oml) was stirred under an atmosphere of hydrogen at 25 ~C for 24 hours. Filtration through celite and removal of solvent under reduced pressure yielded the amine as a golden brown oil (13.2g, 65.7 mmol, 96% ): lH NMR (400 MHz, CDC13) ~ 7.10 (d, lH, ArH), 6.63(d, lH, ArH), 6.50 (dd, lH, ArH), 3.50 (br s, 2H, NH2), 1.65 (br s, 4H, CH2)~ 1.28 (s, 6H, CH3), 1.26(s, 6H, CH3).
A solution of 2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (3 .Og, 14.8 mmol) and acrylic acid (l.Og, 14.8 rnmol ) in toluene (60ml) was heated to reflux for 14 hours. Removal of solvent under reduced pressure yielded a viscous brown oil (3.0g, 10.9 mmol, 74% ): lH NMR (400 MHz, CDC13) ~ 7.16 (d, lH, ArH), 6.62 (d, lH, ArH), 6.54 (dd, lH, ArH), 3.48 (t, 2H, N-CH2), 2.68 (t, 2H~cH2)~ 1.67 (br s, 4H, CH2), 1.28 (s, 6H, CH3), 1.26(s, 6H, CH3).
2-amino-3 -(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalene)-propionic acid ( 3 . Og, 10.9 mmol ) was dissolved into PPA (lOOml) and stirred at 100 ~C for 16 hours. The red reaction mixture was poured onto ice (200 g), neutralized by addition of sodium carbonate DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

and extracted with ethyl acetate. Removal of solvent under reduced pressure yielded a yellow semisolid. Column chromatography (10% EtOAc/Hex) gave the desired product as a yellow solid (2.2g, 8.6 mmol, 79% ): lH NMR (400 MHz, CDC13) o 7.80 (s, lH, ArH), 6.60 ~s, lH, ArH), 3.55 (t, 2H, N-CH2), 2.68 (t, 2H,CH2), 1.65 (br s, 4H, CH2), 1.28 (s, 6H, CH3), 1.26(s, 6H, CH3).
A solution of 6,6,9,9-tetramethyl-2,3,6,7,8,9-tetrahydro-lH-benzo~g] quinoline-4-one (255mg, 1.0 mmol), iodoethane (2.0g, 12.4 mmol ), and anhydrous potassium carbonate (1.4g, 10.0 mmol) in DMA (50ml) was stirred at 50-60 ~C for 48 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. Removal of solvent under 10 reduced pressure yielded a yellow/brown oil (150mg) which partially solidified on standing.
Column chromatography (10% -20 % EtOAclHex) gave the desired product as a brightyellow/green solid (80mg, 0..28 mmol, 28% ): lH NMR (400 MHz, CDC13) o 7.85 (s, lH, ArH), 6.63 (s, lH, ArH), 3.40 (q, 2H, N-cH2)~ 3.38 (t, 2H, N-cH2)~ 2.65 (t, 2H,CH2), 1.65 (br s, 4H, CH2), 1.30 (s, 6H, CH3), 1.28(s, 6H, CH3), 1.16 (t, 3H, CH3) Procedures similar to those in Examples 1 and 2 afforded the title compound 147b as a orange serni-solid material. The final product was purified by HPLC ( 90/10 MeOH/H2O) to give a yellow solid.: lH NMR (400 MHz, CDCl3) ~ 7.46 (s, lH, ArH), 7.05 (dd, lH, CH), 6.62 (d, lH, CH), 6.56 (s, lH, ArH), 6.42 (d, lH, CH), 5.83 (br s, lH, CH), 3.38 (q, 2H, N-CH2), 3.26 (t, 2H, N-CH2), 2.83 (t, 2XcH2)~ 2.40 (s, 3X CH3), 1.67 (br s, 4H, CH2), 1.28 (s, 6H, CH3), 1.26(s, 6X CH3), 1.15 (t, 3H, CH3).

Preparation of compound 148b according to Scheme XIII
T-butyl-4-(5-carboxy-penta-2E-4E-dieneylidene)-6,6,9,9-tetramethyl-3,4,6,7,8,9-he~ahydro-2~I-benzo[g] quinolin-1-carbo~ylate (structure 54, where Rl, R2, R3, R4, and R1g are methyl; Rs, R7, Rg, Rg, R1o, R26, R27, R28, and R2g, are hydrogen; R1s is hydroxy; X, Y are carbon, Z is N-1-carboxylic acid tert-butyl ester; m = n = 1) The title compound was prepared as in Example 73 except for the nitrogen alkylation step which involved the use of t-butylchloroformate. Following the standard hydrolysis procedure of Example 2 gave 50 mg of the title compound obtained as a yellow orange oil.

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Column chromatography (40~/O Diethyl ether/Hexane) gave the desired product as a yellow film: lH N~ (400 MHz, CDC13) o 7.57 (s, lH, ArH), 7.43 (s, lH, ArH), 6.98 (dd, lH, CH), 6.72 (d, lH, CH), 6.45 (d, lH, CH), 5.80 (s, lH, CH), 3.80 (t, 2H, N-CH2), 2.90 (t, 2X CH2), 2.38(s, 3H, CH3), 1.70 (br s, 4H, CH2)~ 1.50 (s, 9H, CH3), 1.30 (s, 6H, CH3), 1.26(s, 6X CH3).
.

Preparation of compound 149b accordin~ to Scheme XVI
(2E,4E)-3-methyl-(6,6,9,9-tetramethyl-2,3,6,9-tetrahydronaphtho[2,3-b]-[1,4]oxazin-4-yl)-he~a-2,4-dienoic acid (structure 68, where Rl, R2, R3, R4, and Rlg are methyl; Rs, R6, R7, Rg, Rg, Rlo, R26, R27, R28~ and R2g, are hydrogen; Rls is hydroxy; X, Y are carbon, W is nitrogen, Z is oxygen; m = n = 1) To a solution of 6-6-9-9-tetramethyl-6,9-dihydro-4H-naphtho[2,3-b][1,4]oxazin-3-one (400 mg, 1.5 mmol) [prepared by Friedel Crafts alkylation/~nn~ tion of 2H-1,4-benzoxazin-3-(4H)-one with 2,5-dichloro-2,5-dimethyl hexane in the presence of all~minllm chloride at ambient temperatue (24~C) in dichloromethane] in THF at ambient temperature was added LiAlH4 (4.6 rnl, 4.6 mmol). The reaction mixture was allowed to stir and then was heated to 80~C for 30min. The reaction mixture was poured over saturated sodium potassium tartrate solution (100 ml), extracted with EtOAc (100 ml), dried with anhydrous MgS04 (0.5 g), and concentrated to give 6,6,9,9-tetramethyl-3,4,6,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazine (300 mg, 70% yield of theory): lH NMR (400 MHz, CDC13) o 6.70 (s, lH, benzylic), 6.52 (s, lH, benzylic), 4.23 (t, 2H, J = 2.8, 1.6 Hz, ring CH2), 3.39 (t, 2H, J = 4.4, 6.8 Hz, ring CH2), 1.63 (s, 4H, 2 CH2), 1.22 (s, 12H, 4 CH3).
To a solution of ethyl-6-bromohexa-2,4-dienoate (45 mg, 0.19 mmol) in THF at ambient temperature was added NaH (4 mg, 0.14 mmol) under N2(gas). The solution was stirred for 10 min and then added to 6,6,9,9-tetramethyl-3,4,6,9-tetrahydro-2H-naphtho[2,3-b][l,4]oxazine (24 mg, 0. lmmol) at ambient temperature. The reaction was then heated to ' 65~C overnight. The reaction was then quenched over saturated NH4Cl solution (100 ml) extracted with EtOAc (100 ml), dried with anhydrous MgSO4 (0.5 g), and concentrated.
The product ran on prep tlc plates (20% EtOAc/ Hexane) to give ethyl-3-methyl-(6,6,9,9-DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

tetramethyl-2,3,6,9-tetrahydronaphtho [2,3-b][1,4]oxazin-4-yl)hexa-2,4-dienoate (25 mg, 89% yield oftheory): lHNMR (400 MHz, CDC13) o 6.71 (s, lX benzylic), 6.56 (s, lH, benzylic), 6.31 (d, lH, J= 15.6 Hz, olefinic), 6.17 (dt, lH, olefinic), 5.57 (s, lH, olefinic), 4.25 (t, 2H, J = 4, 4 Hz, N-CH2), 4.17 (q, 2H, CH2CH3); 3 .95 (d, 2H, J = 6.8 Hz, N-CH2), 3.28 (t, 2H, J = 4 Hz, ring CH2), 2.27 (s, 3H, CH3), 1.63 (s, 4H, 2CH2), 1.28 (t, 3H, CH3), 1.22 (s, 6H, 2CH3), 1.21 (s, 6H, 2CH3).
Standard hydrolysis conditions, as in Example 2 were used to obtain 3-methyl-(6,6,9,9-tetramethyl-2,3,6,9-tetrahydronaphtho[2,3-b][1,4]oxazin-4-yl)hexa-2,4-dienoic acid (12.5 mg, 88% oftheory): lH NMR (400 MHz, CDC13) ~ 6.71 (s, lH, benzylic), 6.56 (s, lH, benzylic), 6.31 (d, lH, J = 15.6 Hz, olefinic), 6.17 (dt, lH, olefinic), 5.57 (s, lH, olefinic), 4.25 (t, 2H, J = 4, 4 Hz, N-cH2)~ 3.95 (d, 2H, J = 6.8 Hz, ring CH2), 3.28 (t, 2H, J = 4 Hz, ring CH2), 2.27 (s, 3H, CH3), 1.63 (s, 4H, 2cH2)~ 1.22 (s, 6H, 2CH3), 1.21 (s, 6H, 2CH3).

Preparation of compound 150b accordin~ to Scheme XVI
(2E,4E)-3-methyl-6-oxo-6-(6,6,9,9-tetrahydro-2,3,6,9-tetrahydro-naphthol2,3-bl[1,4]o~azin-4-yl)he~a-2,4-dienoic acid (structure 69, where Rl, R2, R3, R4, and R1g are methyl; Rs, R6, R7, Rg, Rg, R1o, R26, R27, R2g, and R29, are hydrogen; Rls is hydroxy;
X, Y are carbon, W is nitrogen, Z is oxygen; m= n = 1).
To a solution of 6,6,9,9-tetramethyl-3,4,6,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazine (prepared in Example 75, 100 mg, 0.408 mmol) was added hexa-2,4-dienedioic acid mono ethylester (90 mg, 0.489 mmol) in dichloromethane, at ambient temperature. To this solution was added DMAP (50 mg, 0.489 mmol), CSA (47 mg, 0.204 mmol), and DCC (100 mg, 0.489 mmol). The reaction was stirred at ambient temperature for 30 min. EtOAc was added, and the reaction mixture was filtered and evaporated. Prep TLC
was used (20% EtOAc / Hexane) to give ethyl-3-methyl-6-oxo-6-(6,6,9,9-tetrahydro-2,3,6,9-tetrahydro-naphtho[2,3-b][1,4]oxazin-4-yl)hexa-2,4-dienoate (30 mg, 40% yield of :- theory): lH NMR (400 MHz, CDC13) o 7.40 (d, lH, olefinic), 6.90 (br s, lH, benzylic), 6.86 (d, lH, olefinic), 6.85 (s, lH, benzylic), 6.09 (d, lH, olefinic), 4.29 (t, 2H, ring CH2), 4.21 DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

(q, 2H, CH2), 4.04 (t, 2H, ring CH2) 2.25 (s, 3H, CH3), 1.62(s, 4H, 2cH2)~ 1.30 (t, 3H, CH3), 1.28(s, 6H1 2CH3), 1.22 (s, 6H, 2CH3).
Standard hydrolysis conditions, as in Example 2, were used to obtain 3-methyl-6-oxo-6-(6,6,9,9-tetrahydro-2,3,6,9-tetrahydronaphtho[2,3-b][1 ,4]oxazin-4-yl)hexa-2,4-S dienoicacid(18 mg, 40%yieldoftheory): 1HNM:R(400MHz, CDCl3) 7.43 (d, lH, olefinic), 6.92 (br s, lH, benzylic), 6.90 (d, lH, olefinic), 6.86 (s, iH, benzylic), 6.13(s, lH, olefinic), 4.31 (t, 2H, ring CH2)~ 4.04 (t, 2H, ring CH2)~ 2.27 (s, 3H, CH3), 1.67 (s, 4H, 2CH2), 1.26 (s, 6H, 2CH3), 1.22 (s, 6H, 2CH3).

Preparation of compound 151a according to Scheme XVII
(2E,4E)-3-methyl-6-(6-ethyl-1,9,9-trimethyl-7-oxo-2,3,6,7,8,9-hexahydro-llI-pyrido[2,3-g]quinolin-4-ylidene)hexa-2,4-dienoic acid (structure 76, where R1 is ethyl;
R2, R3, R4, R1g and R24 are methyl; Rs, R7, R8, Rg, R1o and R28 are hydrogen; R1s is hydroxy; X, Z are N; Y is carbon; m = n = 1) To a solution of aniline (19.73g, 0.212mol) in CH2cl2 (200ml) at O ~C was added dropwise 3,3-dimethyl acryloyl chloride (25.0g, 0.212mol) and triethylamine (21.4g, 0.212mol) at equal rates. This mixture was allowed to warm to 25 ~C and stirred at for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate.
Removal of solvent under reduced pressure yielded the amide as a fine white fibrous solid (28.9g, 0.1 65mol, 78%). 1H NMR (400 MHz, CDCl3) o 7.52 (br d, 2H, ArH), 7.40 (br s, lH, NH), 7.28 (t, 2H, ArH), 7.05 (t, lH, ArH), 5.72 (s, lH, CH), 2.20 (s, 3H, CH3), 1.86 (s, 3H, CH3).
To a solution of 3-methylbut-2-enoic acid phenylamide (lO.Og, 0.057mol) in CH2Cl2 (lSOml) at 25 ~C was added ~lllmimlm chloride (5.0g, 0.037mol). This mixture was heated to reflux and stirred for 6 hours. The reaction mixture was poured onto ice (30g) extracted with CH2Cl2 . Removal of solvent under reduced pressure yielded the lactam as an off white-solid (9.5g, 0.054mol, 95%): lH NMR (400 MHz, CDCl3) o 9.10 (br s, lH, NH), DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

7.32 (d, lH, ArH), 7.18 (t, lH, ArH), 7.05 (t, lH, ArH), 6.85 (d, lH, ArH), 2.25 (s, 2H, CH2), 1.35 (s, 6H, CH3).
4,4-dimethyl-3,4-dihydro-lH-quinolin-2-one (4.5g, 0.0257mol) was dissolved in sulfuric acid (30ml) and cooled to 10 ~C. To this solution was added dropwise fuming nitric ~ ; S acid(2.16g, 0.031rnol). This mixture was stirred at 10 ~C for 30 min and at 25 ~C for 2 hours. The reaction mixture was poured onto ice (50g) and the solid nitro lactam was filtered and rinsed with saturated sodium bicarbonate and water. The nitro lactam was collected as a fine brown powder (S.Sg, 0.025mol, 97%). lH NMR (400 MHz, CDC13) ~ 8.76 (br s, lH, NH), 8.21 (d, lH, ArH), 8.10 (dd, lH, ArH), 6.90 (d, lH, ArH), 2.57 (s, 2H, CH2), 1.40 (s, 6H, CH3).
A solution of 4,4-dimethyl-6-nitro-3,4-dihydro-lH-quinolin-2-one (3.0g, 0.0136mol) in THF (20ml) was added to a solution of sodium hydride (420mg, 0.017mol) in THF (30ml) at 25 ~C under nitrogen. This mixture was stirred for 1.5 hours and iodomethane (12.8g, 0.082mol) was added all at once. The reaction mixture was heated to 50 ~C for 20 hours, quenched by slow addition of water and extracted with ethyl acetate. Removal of solvent under reduced pressure afforded the ethyl lactam as a brown solid (4.5g). This material was not purified. lH NMR (400 MHz, CDC13) ~ 8.19 (d, lH, ArH), 8.17 (dd, lH, ArH), 7.12 (d, lH, ArH), 4.10 (q, 2H, CH2)~ 2.57 (s, 2H, CH2), 1.35 (s, 6X CH3), 1.27 (t, 3H, CH3).
l-ethyl-4,4-dimethyl-6-nitro-3,4-dihydro-lH-quinolin-2-one (4. lg crude) was suspended in a 75% solution of ethanol\water (20ml). To this mixture was added calcium chloride monohydrate (2.0g, 0.0136mol) and zinc dust (30g,0.461mol). The reaction mixture was heated at reflux for 4 hours and stirred at 25 ~C for an additional 14 hours. The mixture was diluted with water, filtered and extracted with ethyl acetate. Removal of solvent under reduced pressure gave a brown oil (3.5g). Column chromatography (50% EtOAc/hex )afforded the amino lactam as a yellow oil (1.8g, 8.3mmol). lH NMR (400 MHz, CDC13) 6.84 (d, lH, ArH), 6.66 (d, lH, ArH), 6.57 (dd, lH, ArH), 3.97 (q, 2H, CH2), 3.57 (br s, 2H, NH2), 2.43 (s, 2H, CH2), 1.27 (s, 3H, CH3), 1.25 (s, 3H, CH3), 1.23(t, 3H, CH3).
A solution of 6-amino-(1-ethyl-4,4-dimethyl-3,4-dihydro-lH-quinolin-2-one) (750mg, 3.5mmol) and acrylic acid (252mg, 3.5mmol ) in toluene (lOml) was heated to DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

reflux for 28 hours. Removal of solvent under reduced pressure gave a brown oil (9OOmg).
Column chromatography (5% -10% MeOH/ CHC13) afforded the amino lactam as a yellow oil (597mg, 2. lmmol, 60% ): lH NMR (400 MHz, CDC13) ~ 6.90(d, lH, ArH), 6.63(d, lH, ArH), 6.54 (dd, lH, ArH), 3.98(q, 2H, CH2)~ 3.46 (t, 2H, N-cH2)~ 2.70 (t, 2H, CH2), 2.45 S (s, 2H, CH2), 1.27 (s, 3H, CH3), 1.25 (s, 3H, CH3), 1.22(t, 3H, CH3).
3-(1-ethyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl-amino)propionic acid (597mg, 2. lmmol) was dissolved into PPA (5ml ) and stirred at 100 ~C for 16 hours. The red reaction mixture was poured onto ice (20g), neutralized by addition of sodium carbonate and extracted with ethyl acetate. Removal of solvent under reduced pressure gave the 10 tricyclic ketone as a yellow semi-solid. Column chromatography (3% MeOH/ CHC13) afforded the desired product as a yellow oil (340mg, 1.3 mmol, 62% ) lH NMR (400 MHz.
CDC13) ~ 7.50(s, lH, ArH), 6.63 (s, lH, ArH), 4.33 (br s, lH, NH), 4.03 (q, 2H, CH2), 3.60 (t, 2H, N-CH2), 2.70 (t, 2H, CH2)~ 2.43 (s, 2H, CH2)~ 1.27 (s, 3H, CH3), 1.25 (s, 3H, CH3), 1.22(t, 3H, CH3) Conversion of the tricylic ketone 53 to the title compound 76 followed the procedures given in Examples 1 and 2. TLC (50% EtOAc/hex) afforded the desired 6-(6-ethyl- 1, 9, 9-trimethyl-7-oxo-2, 3, 6, 7, 8, 9-hexahydro- 1 H-pyrido [2, 3 -g] quinolin-4-ylidene)-3 -methyl-hexa-2,4-dienoic acid (5mg) as a red orange film. lH NMR (400 MHz, CDC13) 7.00 (dd, lX CH), 6.84 ~s, lH, ArH), 6.63 (s, lX ArH), 6.57 (d, lH, CH), 6.37(d, lH, CH), 5.79 (s,lH, CH), 3.37 (q, 2H, CH2)~ 3.20 (t, 2H, N-cH2)~ 3.10 (t, 2H, CH2), 2.83 (s, 3H, N-CH3), 2.80 (s, 3H, CH3), 2.38 (s, 2H, CH2)~ 1.35 (s, 6H, CH3), 1.25 (t, 3H, CH3).

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Preparation of compound 152b according to Scheme XVIII
E-4-[N'-(5,5,8,8-tetramethyl-3,4,5,6,7,8-he~ahydro-21 [-anthracen-1-ylidene)-hydrazino]benzoic acid (structure 78, where Rl, R2, R3, and R4 are methyl; Rs, R6 R7, R8, Rg, Rlo, R26, R27, R28 and R29 are hydrogen; R15 is hydroxy; R14 is 4-benzoic acid,W is N, X, Y, Z are carbon; m = n = 1) The title compound was prepared from the tricyclic ketone 60 prepared in Example1. A solution of 6,6,9,9-tetramethyl-1,2,6,7,8,9-hexahydro-3H-anthracen-1-one (100 mg, 0.39 mmol) and 4-hydrazinobenzoic acid (62.5 mg, 0.41 mmol) and one drop of conc.
hydrochloric acid in 5 mL of ethanol was heated to reflux for 3.5h, then cooled to room temperature. The solvent was removed in vaCuo to a solid residue that was subjected to flash chromatography (silica gel, hexanes-ethyl acetate, 70:30) which gave 40 mg (26%) of the desired product 1 as a light yellow solid. The geometry of the hydrazone was determined by NOE experiments. 1H NMR (400 MHz, CDCl3) ~ 8.16 (s, lH, hydrazone N-H), 8.05 (d, J = 8.8 Hz, 2H, benzoic acid-3,4-H's), 7.64 (s, lH, 10-H), 7.18 (d, J= 8.8 Hz, 2H, benzoic acid-1,5-H's), 7.06 (s, lH, 5-H), 2.74 (t, J = 6.0 Hz, 2H, 2-CH2), 2.59 (t, J = 6.Hz, 2H, 4-CH2), 2.01 (m, 2H, 3-CH2), 1.70 (s, 4H, 7,8-CH2's), 1.36 (s, 6H), 1.29 (s, 6H).

Preparation of compound 153b accordin~ to Scheme XVIII
E-4-[N'-(6,6,9,9-tetramethyl-2,3,6,7,8,9-he~ahydro-benzo[g]chromen-4-ylidene)-hydrazino]benzoic acid (structure 78, where R1, R2, R3, and R4 are methyl; Rs, R6, Rg, and Rlo are hydrogen; R15 is hydroxy; R14 is para-amino benzoate, G is C, W is N, X, Y, are carbon, Z is O, m = n = 1) A solution of 1,2,3,4-tetrahydro-6,6,9,9-tetramethyl naphto (2,3) pyran-4-one (56 mg, 0.215 mmol) and 4-hydrazinobenzoic acid (50 mg, 0.323 mmol) and one drop of conc.
hydrochloric acid in 2 mL of ethanol was heated to reflux for 3.5h, then cooled to rt. The solvent was removed in vacuo to afford a solid residue that was subjected to flash chromatography (silica gel, hexanes-ethyl acetate, 60:40) to give 1.7 mg (2%) ofthe desired product 4 as a light yellow solid. lH NMR (400 MHz, CDCl3) o 8.05 (d, J = 7.9 Hz, 2H, DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

benzoic acid-3,4-H's), 8.04 (s, lH, hydrazone N-H), 7.53 (s, lH, 5-H), 7.18 (d, J = 7.9 Hz, 2H, benzoic acid-1,5-H's), 6.84 (s, lH, 10-H), 4.30 (t, 2H, J = 6.0 Hz, 2-CH2), 2.75 (t, J =
6.0 Hz, 2H, 3-CH2), 1.69 (s, 4H, 7,8-CH2's), 1.35 (s, 6H), 1.27 (s, 6H).
.
E,YAMPLE 80 Preparation of compound 154b according to Scheme XVII
(2E,4E)-3-methyl-6-(6-ethyl-1,9,9-trimethyl-2,3,6,9-tetrahydro-lE~-pyridol2,3-glquinolin-4-ylidene)hexa-2,4-dienoic acid (structure 77, where Rl is ethyl; R3, R4, Rlg and R24 are methyl; R5, R7, R8, Rg, Rlo and R28 are hydrogen; Rls is hydroxy; X, Z are 10 N; Y is carbon; m = n = 1) The title compound was prepared as a by-product from the synthesis of compound 151b (Example 77). To a solution of 6-ethyl-(1,9,9,-trimethyl-7-oxo-2,3,6,7,8,9-hexahydro-lH-pryido [2,3-g] quinolin-4-ylidene)acetonitrile (50mg, 0.168mol), in anhydrous toluene (4ml) and anhydrous hexanes (14ml) at -78 ~C was added DIBAL in hexanes (0.5ml, 0.5mol). This mixture was stirred at -30 ~C for 3 hours, quenched by slow addition of saturated sodium potassium tatrate, 1 N HCL, and extracted with ethyl acetate. Removal of solvent under reduced pressure afforded a mixture of aldehydes as an red orange oil (50mg).
lH NMR confirmed the presence of aldehyde protons as well as vinyl protons whichcorrespond to enamine formed by partial reduction of the amide. This material was not purified and used crude in subsequent reactions.
Following the standard procedure demonstrated in Examples 1 and 2, the mixture of aldehydes was carried through to the hydrolysis of the ester products. The crude mixture of esters above was hydrolyzed under standard conditions to give a mixture of trienoic acids.
TLC (50% EtOAc/hex) afforded the 6-(6-ethyl-1,9,9-trimethyl-2,3,6,9-tetrahydro-lH-pyrido [2,3-g] quinolin-4-ylidene)-3-methylhexa-2,4-dienoic acid (4mg) as a red film: 1H NMR
(400 MHz, CDC13) d7.10 (dd, lH, CH), 6.84 (s, lX ArH), 6.72 (s, lH, ArH), 6.57 (d, lH, CH), 6.40(d, lH, CH), 6.00 (d, lH, CH), 5.82 (s,lH, CH), 4,42 (d, lH, CH), 3.25 (q, 2H, CH2), 3.23 (t, 2H, N-CH2), 2.90 (t, 2H, CH2), 2.37 (s, 3H, N-CH3), 2.10 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.36 (s, 3X CH3), 1.25 (t, 3H, CH3) DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Evaluation of Retinoid RecePtor Subfamilv Activity Utilizing the "cis-trans" or "co-transfection" assay described by Evans et al., Science~
240:889-95 (May 13, 1988), the disclosure of which is herein incorporated by reference, the retinoid compounds of the present invention were tested and found to have strong, specific 5 activity as either selective RAR agonists, selective R~ agonists, or as pan-agonist activators of both RAR and R~ receptors. This assay is described in further detail in U. S .
Patent Nos. 4,981,784 and 5,071,773, the disclosures of which are incorporated herein by reference.
The co-transfection assay provides a method for identifying functional agonists which 10 mimic, or antagonists which inhibit, the effect of native hormones, and quantifying their activity for responsive I:R proteins. In this regard, the co-transfection assay mimics an in viw systern in the laboratory. Importantly, activity in the co-transfection assay correlates very well with known in vivo activity, such that the co-transfection assay functions as a qualitative and quantitative predictor of a tested compounds in vivo pharmacology. &, e.~., T. Berger et al. 41 J. Steroid Biochem. Molec. Biol. 773 (1992), the disclosure of which is herein incorporated by reference.
In the co-transfection assay, a cloned cDNA for an IR (e.g., human RARa, RAR,~, R~) under the control of a constitutive promoter (e.g., the SV 40 promoter) is introduced by transfection (a procedure to induce cells to take up foreign genes) into a background cell 20 substantially devoid of endogenous IRs. This introduced gene directs the recipient cells to make the IR protein of interest. A second gene is also introduced (co-transfected) into the same cells in conjunction with the lR gene. This second gene, comprising the cDNA for a reporter protein, such as firefly luciferase (LUC), controlled by an appropriate hormone responsive promoter con~ining a hormone response element (HRE). This reporter plasmid 25 functions as a reporter for the transcription-mocl~ tin~ activity of the target l:R. Thus, the reporter acts as a surrogate for the products (mRNA then protein) normally expressed by a gene under control of the target receptor and its native hormone.
The co-transfection assay can detect small molecule agonists or antagonists of target IRs. Exposing the transfected cells to an agonist ligand compound increases reporter activity 30 in the transfected cells. This activity can be conveniently measured, e.g., by increasing luciferase production, which reflects compound-dependent, IR-mediated increases in reporter DOCKET NO. CA 02209134 1997-06-27 016-OOl9~.WO

transcription. To detect antagonists, the co-transfection assay is carried out in the presence of a constant concentration of an agonist to the target IR (e.g., all-z7ans retinoic acid for RARcx) known to induce a defined reporter signal. Increasing concentrations of a suspected antagonist will decrease the reporter signal (e.g., luciferase production). The co-transfection 5 assay is therefore useful to detect both agonists and antagonists of specific IRs.
Furthermore, it deterrnines not only whether a compound interacts with a particular ~, but whether this interaction rnimics (agonizes) or blocks (antagonizes) the effects of the native regulatory molecules on target gene expression, as well as the specificity and strength of this interaction.
The activity of the retinoid compounds of the present invention were evaluated tili7in~ the co-transfection assay according to the following illustrative Example.

Co-transfection assav CV- 1 cells (African green monkey kidney fibroblasts) were cultured in the presence of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% charcoal resin-stripped fetal bovine serum then transferred to 96-well microtiter plates one day prior to transfection.
To determine RAR and/or l~XR agonist activity of the compounds of the present invention, the CV- 1 cells were transiently transfected by calcium phosphate coprecipitation according to the procedure of Berger et al., 41 J.Steroid Biochem. Mol. Biol., 733 (1992) with the following receptor expressing plasrnids: pRShRARoc: Giguere et al., 330 Nature, 624 (1987); pRShRAR,~ and pRShRARr, Ishikawa et al., 4 Mol. Endocrin., 837 (1990);
pRShRXRcc, Mangelsdorfetal., 345 Nature, 224 (1990); and pRSmR~,~ and pRSrn~ , Mangelsdorfetal., 6 Genes & Devel., 329 (1992), the disclosures of which are herein incorporated by reference. Each of these receptor expressing plasmids was co-transfected at a concentration of S ng/well, along with a basal reporter plasrnid at 100 ng/well, the internal control plasrnid pRS-13-Gal at 50 ng/well and filler DNA, pGEM at 45 ng/well.
The basal reporter plasmid D-MTV-LUC (Hollenberg and Evans, 55 Cell. 899 (1988), the disclosure of which is herein incorporated by reference) cont~ining two copies of DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

the TRE-palindromic response element described in Umesono et al., 336 Nature, 262 (1988), the disclosure of which is herein incorporated by reference, was used in transfections for the RARs, and the reporter plasmid CRBPIIFKLUC, which contains an RXRE (retinoid X receptor response element, as described in Mangelsdorf et al., 66 Cell. 555 (1991), the ~ 5 disclosure of which is herein incorporated by reference), was used in transfections for the R~Rs. Each of these reporter plasmids contains the cDNA for firefly luciferase (LUC) under constitutive promoter con~inin~ the appropriate RAR or R~R response element. As noted above, pE~S-B-Gal, coding for constitutive expression of E. coli ~3-galactosidase (13-Gal), was included as an internal control for evaluation of transfection e~ciency and 10 compound toxicity.
Six hours after transfection, media was removed and the cells were washed with phosphate-buffered saline (PBS). Media cont~ining compounds of the present invention in concentrations ranging from 10-12 to 10-5 M were added to the cells. Similarly, the reference compounds all-trans retinoic acid (ATRA)(Sigma Chemical), a known RAR
15 selective compound, and 9-cis retinoic acid (9-cis) (synthesized as described in Heyman et al., ~.ell, 68:397-406 (1992)), a compound with known activity on RXRs, were added at similar concentrations to provide a reference point for analysis of the activity of the compounds of the present invention. Retinoid purity was established as greater than 99% by reverse phase high-performance liquid chromatography. Retinoids were dissolved in 20 dimethylsulfoxide for use in the transcriptional activation assays. Three to four replicates were used for each sample.
A~er 40 hours, the cells were washed with PBS, lysed with a Triton X-100-based buffer and assayed for LUC and 13-Gal activities using a luminometer or spectrophotometer, respectively. For each replicate, the normalized response (NR) was calculated as:
LUC response/~3-Gal rate where ~3-Gal rate = 13-Gal lxlO~5/J3-Gal incubation time.

The mean and standard error of the mean (SEM) of the NR were calculated. Data was plotted as the response of the compound compared to the reference compounds over the -016-0019A.WO

range of the dose-response curve. For the agonist compounds of the present invention, the effective concentration that produced 50% of the maximum response (ECso) was quantified.
The potency (nM) of selected retinoid compounds of the present invention are in Table 1 below.

Table 1: Potency (nM) of selected retinoid compounds of the present invention on RARoc,~,~ and RXRoc,~,~, in comparison to the known RAR-active retinoid compound all-trans retinoic acid (ATRA) and RXR-active retinoid compound 9-cis retinoic acid (9-cis).
I~ARa RAR~ RARr RXRa RXR,~ RXR~
Cmpd. Pot Pot Pot Pot Pot Pot No. nM nM nM nM nM nM
101b 32 8 7 35 55 41 104b na 61 83 18 20 11 106b 84 20 14 na 52 127 109b 28 3 1 2022 64 2267 119b 20 1 1 1659 1145 742 124b 101 33 94 38 37 26 135b 1166 53 47 2783 1979 2531 138b na na na 422 204 301 141b 863 32 12 na na 2930 143b na 466 1877 393 472 247 144b 14 3 2 36 45 40 147b 35 4 1 na 579 1470 152b 651 8 32 na na na
9-cis 220 29 50 195 128 124 na = not active (potency of >10,000 and/or efficacy of < 20%) As can been seen in Table 1, Compounds 101b, 109b, 119b and 144b are extremely potent RAR active, with all compounds displaying activity at less than 10 nM on RAR~ and RARy. Further, Compounds 109b and 119b are RAR selective. In fact, these Compounds are 2 to 10 times more potent than the known RAR active compound ATRA on the RARs. In addition, Compound 104b is a potent and selective RXR compound. Likewise, pan-agonist Compounds 101b, 124b and 144b display superior potency profiles to that ofthe known R~
active pan-agonist compound 9-cis retinoic acid.

, DOCKET NO.CA 02209134 1997-06-27 016-0019A.WO

In addition to the cotransfection data of Example 81, the binding of selected compounds of the present invention to the RAR and RXR receptors was also investigated according to the methodology described in M.F., Boehm, et al., "Synthesis and Structure-5 Activity Relationships of Novel Retinoid X Receptor Selective Retinoids", 37 J Med.
Chem., 2930 (1994); M.F. Boehm, et al., "Synthesis of High Specific Activity [ H]-9-cis Retinoic Acid and Its Application for Identifying Retinoids with Unusual BindingProperties", 37 J. Med. Chem., 408 (1994), and E.A. Allegretto, et al., "Characterization and Comparison of Hormone-Binding and Transactivation Properties of Retinoic Acid and Retinoid X Receptors Expressed in M~mm~ n Cells and Yeast", 268 J. Biol. C.hem., 22625 (1993), the disclosures of which are herein incorporated by reference.
Non-specific binding was defined as that binding rçm~ining in the presence of 500 nM of the appropriate unlabelled compound. At the end of the incubation period, bound from free ligand were separated. The amount of bound tritiated retinoids was determined by liquid 15 scintill~tion counting of an aliquot (700 rnL) of the supernatant fluid or the hydroxylapatite pellet.
After correcting for non-specific binding, IC50 values were deterrnined. The ICso value is defined as the concentration of competing ligand needed to reduce specific binding by 50%.
The ICso value was deterrnined graphically from a log-logit plot of the data. The Ki values were 20 determined by application of the Cheng-Prussof equation to the IC50 values, the labeled ligand concentration and the Kd of the labeled ligand.
The binding activity (Kd in nM) results of selected retinoid compounds of present invention, and the reference compounds ATRA, and 9-cis RA, is shown in Table 2 below.

[rest of page left purposely blank]

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Table 2: Binding (Kd in nM) of selected retinoid compounds of the present invention on RARa"~,~ and RXRa"B,~ proteins in comparison to the known RAR-active retinoid compound all-trans retinoic acid (ATRA) and RXR-active retinoid compound 9-cis retinoic acid (9-cis).
RARa RAR~ RARy RXRa RXR~ RXR)~
Cmpd. Binding Binding Binding Binding Binding Binding No. Kd (nM) Kd (nM) Kd (nM) Kd (nM) Kd (nM~ Kd (nM) 101b 225 299 541 34 30 48 109b 33 68 279 340 332 382 ll9b 24 50 87 246 372 398 138b >1000 >1000 >1000 136 276 508 144b 145 313 494 59 146 85 147b 6 4 8 433 548 724 9-cis 93 97 148 8 15 14 As can be seen in Table 2, the compounds of the present invention show comparable binding to the known RAR active compound ATRA, and the known RXR active compound 9-cis.

Yet another recognized measure of the retinoid activity of the compounds of the present invention is the ornithine decarboxylase assay, as originally described by Verma and Boutwell, 37 Cancer Research 2196 ~1977~, the disclosure of which is herein incorporated by reference.
In Verma & Boutwell original work using retinoic acid, it was established that ornithine decarboxylase (ODC) activity increased in relation to polyamine biosynthesis. In turn, it had previously been established that increases in polyamine biosynthesis is correlated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be mod~ ted. Although all causes of increased OCD activity are yet unknown, it is known that 12-0-tetradecanoylphorbor-13-acetate (TPA) induces ODC activity. Importantly, retinoic acid inhibits this induction of ODC by TPA.
An ODC assay essentially following the procedures set out in 35 Cancer Research 1662 (1975), the disclosure of which is herein incorporated by reference, was used to demonstrate the inhibition of TPA induction of ODC by the compounds of the present invention. The results of this assay on exemplary compounds, and the reference compounds ATRA and (E)-4-[2-(5,6,7,8-DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)- 1 -propenyl]benzoic acid (TTNPB), known RAR
active compounds~ are shown below in Table 3. All values are expressed as the concentration of ~ the indicated compounds in nM required to inhibit the TPA induction of ODC by 80 percent, i.e.
- the ICgo in nM.
-. 5 Table 3: Inhibitory concentration required to inhibit 80% of the maximally observed TPA
induction of ODC (ODC IC80) in nM for selected Compounds of the present invention and reference compounds ATRA and TTNBP.

Compound ODC ICgo (nM) 101a ~91.0 lO.lb 0.78 lO9b 0.08 144b 0.60 ATRA 1.40 Compound 101b, which is the ester of Compound 101a, has been included to show that such ester analogs exhibit retinoid activity. While not being bound to a theory of operation, it is believed that such esters may operate as pro-drugs in vivo, possibly due to the cleavage of the ester to the active acid form of the compounds of the present invention The in vitro affect of selected compounds of the present invention on the recognized cancer cell lines, RPMI 8226, ME 180 and AML-193, obtained from the American Type Culture Collection (ATCC, Rockville, MD), was investigated.
RPMI 8226 is a human hematopoietic cell line obtained from the peripheral blood of 20 a patient with multiple myeloma, and as such is a recognized model for multiple myelomas and related malignancies. Y. Matsuoka, G.E. Moore, Y. Yagi and D. Pres.~m~n, "Production of free light chains of immunoglobulin by a hematopoietic cell line derived from a patient with multiple myeloma", 125 Proc. Soc. Exp. Biol. Med., 1246 (1967), the disclosure of which is herein incorporated by reference. The cells resemble the Iymphoblastoid cells of 25 other human lymphocyte cell lines and secretes ~-type light chains of immunoglobulin.
RPMI 8226 cells were grown in RPMI medium (Gibco) supplemented with 10% fetal bovine serum, glutamine and antibiotics. The cells were m~int~ine~l as suspension cultures grown at DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

37 ~C in a humidified atmosphere of 5% CO2 in air. The cells were diluted to a concentration of 1 x 105/mL twice a week.
ME 180 is a human epidermoid carcinoma cell line derived from the cervix, and assuch is a recognized model for squamous cell carcinomas and related malignancies.'J.A.
5 Sykes, J. Whitescarver, P. Jernstrom, J.F. Nolan and P. Byatt, "Some properties of a new epithelial cell line of human origin", 45 MH-Adenoviridae J. Natl. C,ancerInst., 107 (1970), the disclosure of which is herein incorporated by reference. The tumor was a highly invasive squamous cell carcinoma with irregular cell clusters and no significant ker~tini~tion. ME
180 cells were grown and m~int~ined in McCoy's 5a medium (Gibco) supplemented with
10 10% fetal bovine serum, glutamine and antibiotics. The cells were m~int~ined as monolayer cultures grown at 37 ~C in a humidified atmosphere of 5% CO2 in air.
The AML-193 cell line was established from the blast cells of a patient with leukemia and was classified as M5 Acute Monocytic Lellk~mi~ and as such is a recognized model for leukemias and related m~lign~ncies. G. Rovera, et al., 139 J. Immunol., 3348 (1987), the 15 disclosure of which is herein incorporated by reference. Over 75% of these cells are positive by immlln~-fluorescence for the myelomonocytic antigen CS15. The cells were grown in Iscove's modified Dulbeccos's medium with 5 !lg/mL transferring, 5 !l~/mL insulin and 2 ng/mL rh GM-CSF. The cells were m~int~ined as suspension cultures grown at 37 ~C in a humidified atmosphere of 5% CO2 in air. The cells were diluted to a concentration of 20 1 x 105/mL twice a week.

Incorporation of 3H-Thvmidine Measurement of the level of radiolabeled thymidine incorporated into the above-identified cell lines provides a direct measurement of the antiproliferative properties of the compounds of the present invention The method used for determination of the 25 incorporation of radiolabeled thymidine was adapted from the procedure described by S.
Shrivastav et al., "An in vitro assay procedure to test chemotherapeutic drugs on cells from human solid tumors", 40 CancerRes., 4438 (1980), the disclosure of which is herein incorporated by reference. RPMI 8226 or AML-193 cells were plated in a 96 well round bottom microtiter plate (Costar) at a density of 1,000 cells/well. To appropriate wells, 30 retinoid test compounds were added at the final concentrations indicated for a final volume DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

of 150 IlL/well. The plates were incubated for 96 hours at 37 ~C in a humidified atmosphere of 5% C~2 in air. Subsequently, 1 IlCi of [5'-3H]-thymidine (Amersham, U.K, 43 Ci/mmol specific activity) in 25 ~LL culture medium was added to each well and the cells were - incubated for an additional six hours. The cultures were further processed as described 5 below.
ME 180 cells, harvested by trypsinization were plated in a 96 well flat bottom microtiter plate (Costar) at a density of 2,000 cells/well. The cultures were treated as described above for RPMI 8226 with the following exceptions. After incubation, the supernatant was carefully removed, and the cells were washed with a 0.5 mM solution of 10 thymidine in phosphate buffered saline. ME 180 cells were briefly treated with 50 laL of 2.5% trypsin to dislodge the cells from the plate. Both cell lines were then processed as follows: the cellular DNA was precipitated with 10% trichloroacetic acid onto glass fiber filter mats using a SKATRON multi-well cell harvester (Skatron Instruments, Sterling VA).
Radioactivity incorporated into DNA, as a direct measurement of cell growth, was measured by liquid scintill~tion counting. The mean di~integrations per minute of incorporated thymidine from triplicate wells was determined. The ICso (nM concentration required to inhibit 50% ofthe maximally observed incorporation ofthymidine) for Compounds 101b, 104b, 109b, 119b and 144b ofthe present invention, and reference compounds ATRA and TTNBP are shown below in Tables 4, 5 and 6 for the cell lines RPMI 8226, ME 180 and - 20 AML-193 respectively.

Viability Selected compounds of the present invention were also measured to determine their cytotoxicity on the above-identified cell lines. The procedure used was identical, with only slight modifications, to the assay described in T. Mosmann, "Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays", 65 J.
Immunol. Meth., 55 (1983), the disclosure of which is herein incorporated by reference.
RPMI 8226 or AML-193 cells were plated in a 96 well round bottom microtiter plate (Costar) at a density of 1,000 cells/well. To approp,iate wells, retinoid test compounds were added at the final concentrations indicated for a final volume of 150 ~L/well. The plates were incubated for 96 hours at 37 ~C in a humidified atmosphere of 5% CO2 in air.

DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

Subsequently, 15 IlL of a filter sterilized tetrazolium dye in phosphate buffered saline (Promega, Madison, WI) was added to each well and the cells were incubated for an - additional four hours. Subsequent manipulations of the cultures were as described below.
M:E 180 cells, harvested by trypsinization were plated in a 96 well flat bottom 5 microtiter plate (Costar) at a density of 2,000 cells/well. The cultures were treated as described above for RP~ 8226.
After the four hours incubation, 100 ,uL of a solubilizationistop solution was added - to each well (Promega, Madison, Wl). The plates were allowed to stand overnight at 37 ~C
in the humidified atmosphere. The absorbance at 570 - 600 nm wavelength was recorded for 10 each well using a Biomek ELISA plate reader (Beckman Instruments). The ICso (nM
concentration required to inhibit 50% of the mitochondrial function, and llltim~tely, the viability ofthe cells) for Compounds 101b, 104b, lO9b, ll9b and 144b ofthe present invention, and reference compounds ATRA and Tl~NBP are also shown below in Table 4, 5 and 6 for the cell lines RPMI 8226, ME 180 and AML-193 respectively.

Table 4: Inhibitory concentration required to inhibit 50% of the maximally observed radiolabeled thymidine (TdR ICso) in nM, and inhibitory concentration required to inhibit 50% of the mitochondrial function (MTS ICso) in nM, for selected Compounds of the present invention and reference compounds ATRA and Tl~NBP
20on the RPMI 8226 cell line.

TdR IC50 MTS IC50 Compound (nM) (nM) 101b 6 100 104b 30 90 lO9b 0.05 10 119b 0.5 2.6 144b 0.6 7 5 ~ATRA 102 756 TTNPB 0.2 10 DOCKET ~O. CA 02209134 1997-06-27 016-0019A.WO

Table 5: Inhibitory concentration required to inhibit 50% ofthe maximally observed radiolabeled thymidine (TdR ICso) in nM, and inhibitory concentration required to inhibit 50% of the mitochondrial function (MTS ICso) in nM, for selected Compounds of the present invention and reference compounds ATRA
and TTNBP on the ME 180 cell line.

TdR IC50 MTS IC50 Compound (nM) (nM) 101b 8 75 104b 90 1000 109b 5 100 119b 0.6 2 144b 4 10 TTNPB 0.4 187 Table 6: Inhibitory concentration required to inhibit 50% of the maximally observed radiolabeled thymidine (TdR ICso) in nM, and inhibitory concentration required to inhibit 50% ofthe mitochondrial function (MTS ICso) in nM, for selected Compounds of the present invention and reference compounds ATRA and Tl~NBP
on the AML-193 cell line.

TdR IC50 MTS IC50 Compound (nM) (nM) 101b 37 1000 104b 90 1000 109b 500 1000 119b 0.6 1000 144b 0 6 1000 TTNPB 0.1 1000 The following examples provide illustrative pharmacological composition formulations:
Hard gelatin capsules are prepared using the following ingredients:
Quantity (m~/capsule) Compound 101b 140 Starch, dried 100 Magnesium stearate 10 Total 250 mg DOCKET NO. CA 02209134 1997-06-27 016-0019A.WO

The above ingredients are mixed and filled into hard gelatin capsules in 250 mg quantities.
A tablet is prepared using the ingredients below:
Quantity ~(m~/tablet) Compound 101b 140 Cellulose, microcrystalline 200 Silicon dioxide, fumed 10 Stearic acid 10 Total 360 mg The components are blended and compressed to form tablets each weighing 360 mg.
Tablets, each cont~ining 60 mg of active ingredient, are made as follows:
Quantity (m~/tablet) Compound 101b 60 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone (PVP) (as 10% solution in water) 4 Sodium carboxymethyl starch (SCMS) 4.5 Magnesium stearate 0.5 Talc 1 o Total 150 mg The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of PVP is mixed with the resultant powders, which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50~C and passed through a No. 18 mesh U. S. sieve. The SCMS, magnesium stearate, and talc, previously passed through a No. 60 mesh U. S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Suppositories, each cont~ining 225 mg of active ingredient, may be made as follows:
Compound 101b 225 mg Saturated fatty acid glycerides 2.000 m~
Total 2,225 mg DOCK~ET NO. CA 02209134 1997-06-27 016-0019A.WO

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the miniml-m heat necessary. The mixture is then poured into a suppository mold of normal 2g capacity and allowed to cool.
An intravenous formulation may be prepared as follows:
Compound 101b 100 mg Isotonic saline 1,000 ml Glycerol 100 ml The compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic saline. The solution of the above ingredients is then administered intravenously at a rate of 1 ml per minute to a p.atient.
While in accordance with the patent statutes, description of the plcr~lled embodiments and processing conditions have been provided, the scope of the invention is not to be li~ited thereto or thereby. Various modifications and alterations of the present l S invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention.
Consequently, for an underst~n~lin~ of the scope of the present invention, reference is made to the following claims.

Claims (42)

claims
1. A tricyclic compound of the formula:

(III) wherein, R1 through R4 each independently are hydrogen, a C1 - C6 alkyl, or a C7 - C15 arylalkyl;

R9 and R10 each independently are hydrogen, a C1 - C6 alkyl, F, Cl, Br, NR11R12,NO2 or OR13, where R11 and R12 each independently are hydrogen, a C1 - C8 alkyl, a C7 - C15 arylalkyl, a C1 - C8 acyl, provided that only one of R11 or R12 can be acyl, or R11 and R12 taken together are a C3 - C6 cycloalkyl, and where R13 is hydrogen or a C1 - C8 alkyl or a C7 - C15 arylalkyl;
R14 represents:

where R15 is OR16 or NR17R18, with R16 being hydrogen, a C1 - C6 alkyl or a C7 - C15 arylalkyl, and with R17 and R18 each independently being hydrogen, a C1 - C6 alkyl, a C7 - C15 arylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C3 - C6 cycloalkyl, provided that R18 must be hydrogen when R17 is aryl or hydroxyaryl, R19 is a C1 - C5 alkyl, and A is O, S or NR20, where R20 is a hydrogen, C1 - C6 alkyl or a C7 - C15 arylalkyl;

X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either R1 and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of R1 and R2 or R3 and R4 respectively, do not exist;

V is C or N, provided, however, that when V is N, then no double bond exists adjacent to V;
G is C or N, provided G cannot be C when W is C;
m is 0 or 1 carbon atoms;
n is 0, 1 or 2 carbon atoms;

the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then one each of R5 and R6 or R7 and R8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis (Z) or trans (E) configuration.
2. A compound according to claim 1, selected from the group consisting of (2E,4E)-3-methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1H-cyclopenta [a]naphthalen-3-ylidene]hexa-2,4 dienoic acid; ethyl (2E,4E)-3-methyl-6-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1H-cyclopenta[a]naphthalen-3-yl]hexa-2,4-dienoate;(2E,4E3)-3-methyl-6-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1H-cyclopenta [a]naphthalen-3-yl)hexa-2,4 dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethylcyclopenta[f]naphthalen-4-ylidene]hexa-2,4-dienoate;
(2E,4E)-3-methyl-6-[(Z)-1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethylcyclopenta [f]naphthalen-4-ylidene]hexa-2,4 dienoic acid and ethyl (2E,4E)-3-methyl-6(7,7,10,10-tetrahydro-5,5,8,8 tetramethyl)benzo[f]quinolin-4-yl)hexa-2,4-dienoate.
3. A tricyclic compound of the formula:

(I) OR

(IV) wherein, R1 through R4 each independently are hydrogen, a C1 - C6 alkyl, or a C7 - C15 arylalkyl;
R5 through R8 each independently are hydrogen, a C1 - C6 alkyl or at least two of R5 through R8 taken together are a C3 - C6 cycloalkyl:
R9 and R10 each independently are hydrogen, a C1 - C6 alkyl, F, Cl, Br, NR11R12, NO2 or OR13, where R11 and R12 each independently are hydrogen, a C1 - C8 alkyl a C7 - C15 arylalkyl, a C1 - C8 acyl, provided that only one of R11 or R12 can be acyl, or R11 and R12 taken together are a C3 - C6 cycloalkyl, and where R13 is hydrogen or a C1 - C8 alkyl or a C7 - C15 arylalkyl;

R14 represents; 127 where R15 is OR16 or NR17R18, with R16 being hydrogen, a C1-C6 alkyl or a C7-C15 arylalkyl, and with R17 and R18 each independently being hydrogen, a C1-C6 alkyl, a C7 -C15 arylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C3-C6 cycloalkyl, provided that R18 must be hydrogen when R17 is aryl or hydroxyaryl, R19 is a C1-C5 alkyl, and A is O, S or NR20, where R20 is a hydrogen, C1-C6 alkyl or a C7-C15 arylalkyl;

R26 through R29 each independently are hydrogen or a C1-C6 alkyl, or taken together than one each of R26 and R27 or R28 and R29 respectively, form a carbonyl group;
X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either R1 and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of R1 and R2 or R3 and R4 respectively, do not exist;
Z is O, S, CR22R23 or NR24, where R22 through R24 each independently are hydrogen or a C1-C6 alkyl or R22 and R23 taken together are a C3-C6 cycloalkyl;

W is N or CR25, where R25 is hydrogen or a C1 - C6 alkyl;
V is C or N, provided, however, that when V is N, then no double bond exists adjacent to V;
G is C or N, provided G cannot be C when W is C;
m is 0 or 1 carbon atoms;
n is 0, 1 or 2 carbon atoms;

the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then one each of R5 and R6 or R7 and R8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis (Z) or trans (E) configuration.
4. A tricyclic compound of the formula:

(II) OR

(V) (VI) wherein, R1 through R4 each independently are hydrogen, a C1 - C6 alkyl, or a C7 - C15 arylalkyl;
R5 through R8 each independently are hydrogen, a C1 - C6 alkyl, or at least two of R5 through R8 taken together are a C3 - C6 cycloalkyl;
R9 and R10 each independently are hydrogen, a C1 - C6 alkyl, F, Cl, Br, NR11R12, NO2 or OR13, where R11 and R12 each independently are hydrogen, a C1 - C8 alkyl, a C7 - C15 arylalkyl, a C1 - C8 acyl, provided that only one of R11 or R12 can be acyl, or R11 and R12 taken together are a C3 - C6 cycloalkyl, and where R13 is hydrogen or a C1 - C8 alkyl or a C7 - C15 arylalkyl;

R14 represents:

where R15 is OR16 or NR17R18, with R16 being hydrogen, a C1 - C6 alkyl or a C7 - C15 arylalkyl, and with R17 and R18 each independently being hydrogen, a C1 - C6 alkyl, a C7 - C15 arylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C3 - C6 cycloalkyl, provided that R18 must be hydrogen when R17 is aryl or hydroxyaryl, R19 is a C1 - C5 alkyl, and A is O, S or NR20, where R20 is a hydrogen, C1 - C6 alkyl or a C7 - C15 arylalkyl;
R21 represents:

where R15, R19, and A have the same definitions given above;
R26 through R29 each independently are hydrogen or a C1 - C6 alkyl, or taken together then one each of R26 and R27 or R28 and R29 respectively, form a carbonyl group;
X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either R1 and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of R1 and R2 or R3 and R4 respectively, do not exist;
Z is O, S, CR22R23 or NR24, where R22 through R24 each independently are hydrogen or a C1 - C6 alkyl or R22 and R23 taken together are a C3 - C6 cycloalkyl;

W is N or CR25, where R25 is hydrogen or a C1 - C6 alkyl;
V is C or N, provided, however, that when V is N, then no double bond exists adjacent to V;
G is C or N, provided G cannot be C when W is C;
m is 0 or 1 carbon atoms;
n is 0, 1 or 2 carbon atoms;
q is 1 or 2 carbon atoms;
p is 0, 1 or 2 carbon atoms;
the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then one each of R5 and R6 or R7 and R8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis (Z;) or trans (E) configuration.
5. A compound according to claims 1, 3 or 4 selected from the group consisting of ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-2,3-5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]napthalen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-2,3-5,6,7,8-hexahydro-5,5,8,8,-tetramethyl-cyclopenta[b]naphthalen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcycopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetra-cyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-(2,3,6,7,8,9-hexahydro-2,2,6,6,9,9-hexamethylbenzo[b]-chromen-4-ylidene)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(Z)-2,3,5,6,7,8-hexahydro-3,5,5,8,8-pentamethyl-cyclopenta[b]naphthalen-1-ylidene]hexa-2,4,-dienoic acid; (2E,4E)-3-methyl-6-[(Z)-3,5,6,7-tetrahydro-5,5,7,7-tetramethyl-2H-5-indacen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]naphthalen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(E)-2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]naphthalen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]-5-ylidene]hexa-2,4-dienoic acid; ethyl (2Z,4E)-3-methyl-6-[(E)-l33 1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoate; (2Z,4E)-3-methyl-6-[(E)-1,2,3,6,7,8-hexahydro-1,1,3,3-tetramethylcyclopenta[b]naphthalen-5-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl 6-(E)-[4,4,6,6,9,9-hexamethyl-1,2,3,4,5,6,7,8-octahydroanthracen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E,6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoate; ethyl (2E,4E,6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoate; ethyl (2Z,4E,6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoate; (2Z, 4E, 6E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptene-10-yl]hexa-2,4,6-trienoic acid;
(2E,4E)-3-methyl-6-[(E)-3,5,6,7-tetrahydro-5,5,7,7-tetramethyl-2H-5-indacen-1-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(E)-53,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; (2Z,4E)-3-methyi-6-[(E)-3,4,5,6,7,8-hexahydro-10-nitro-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(E) 2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-ylidene]hexa-2,4-dienoic acid; (2Z,4E)-3-methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-yliden]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(E)-,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]chromen-4-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoic acid;
(3E, 5E)-3-methyl-6-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-3,5-dienoic acid; ethyl (2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethyl-anthracen-1-yl)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(1,2,3,5,6,7,8-heptahydro-5,5,8,8-tetramethylcyclopenta[b]napthalen-1-yl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-1,2,3(5,6,7,8-heptahydro-5,5,8,8-tetramethyl-cyclopenta[b]naphthalen-1-yl]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[1,2,3,4,7;8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4-dienoic acid; ethyl (2Z,4E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthoeyeloheptan-10-yl]hexa-2,4-dienoate; (2Z,4E)-3-methyl-6-[1,2,3,4,7,8,9,10-oetahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4-dienoie acid; (2Z,4E)-3-methyl-6-[1,2,3,4,7,8,9,10-octahydro-1,1,4,4-tetramethyl-6H-naphthocycloheptan-10-yl]hexa-2,4-dienoic acid;(2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-2,2-dimethylpyran-4-yl]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3-b)-pyran-4-yl]hexa-2,4-dienoic acid; (2Z,4E)-3-methyl-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl-(2,3 -b )-pyran-4-yl]hexa-2,4-dienoic acid; (+)-(2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-oetahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoic acid; (-)-(2E,4E)-3-methyl-6-(1,2,3,4,5,6,7,8-octahydro-5,5,8,8-tetramethylanthracen-1-yl)hexa-2,4-dienoic acid; methyl (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-octahydro-6, 6, 9, 9-tetramethylanthracen-1-yl)hex-2-enoate; (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthracen-1-yl)hex-2-enoic acid; (2E)-3-methyl-6-(1,2,3,4,6,7,8,9-oetahydro-6,6,9,9-tetramethylanthracen-1-yl)hex-2-enoie acid;
(2E, 4E) -3-methyl-6-[(E)-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1H-cyclopenta[a]naphthalen-3-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1H-cyclopenta[a]naphthalen-3-yl]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1H-cyelopenta[a]naphthalen-3-yl)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-[(Z)-1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethylcyclopenta[f]naphthalen-4-ylidene]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[(Z)-1,2,3,4,7,8,9-heptahydro-7,7,9,9-tetramethylcyclopenta[f]naphthalen-4-ylidene]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(7,7,10,10-tetramethyl-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-6]-azepinyl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[7,7,10,10-tetramethyl-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-6]azepin-yl)hexa-2,4-dienoic acid; ethyl 3-methyl-6-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-yl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-[3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-yl)hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-oxo-6-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl(2,3)naphthyl [b]piperidin-1-yl]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-oxo-6-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-yl)hexa-2,4-dienoic acid;

ethyl (2E,4E)-3-methyl-6-oxo-6-[(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl)benzo[f]indol-1-yl]hexa-2,4-dienoate; (2E,4E)-3-methyl-6-oxo-6-[(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethyl)benzo-[f]-indol-1-yl]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylbenzo[f]indol-1-yl]-hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylbenzo[f]indol-1-yl]hexa-2,4-dienoic acid; ethyl (2E,4E)-3-methyl-6-(7,7,10,10-tetrahydro-5,5,8,8-tetramethyl)benzo[f]quinolin-4-yl)hexa-2,4-dienoate; (2E,4E)-3-methyl-6-(1,2,3,4,7,8,9,10-octahydro-7,7,10,10-tetramethylbenzo[f]quinolin-4-yl)hexa-2,4-dienoic acid; (2E, 4E)-3-methyl-6-[(Z)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl(2,3-b-pyran-4-ylidene]hexa-2,4-dienoic acid;
(2E,4E)-3-methyl-6-[(E)-3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; Ethyl-(2E,4E)-3-methyl-6-[(Z)-N-acetyl-3,4,5,6,7,8-hexahydro-10-amino-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoate;(2E,4E)-3-methyl-6-[(Z)-N-acetyl-3,4,5,6,7,8-hexahydro-10-amino-5,5,8,8-tetramethyl-2H-anthracen-1-ylidene]hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-[(E)1-ethyl-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydro-1H-benzo[g] quinolin-4-ylidene]hexa-2,4-dienoic acid; T-butyl-4-(5-carboxy-penta-2E-4E-dieneylidene)-6,6,9,9-tetramethyl-3,4,6,7,8, 9-hexahydro-2H-benzo[g]quinolin-1-carboxylate; (2E,4E)-3-methyl-(6,6,9,9-tetramethyl-2,3,6,9-tetrahydronaphtho[2,3-b]-[1,4]oxazin-4-yl)-hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-oxo-6-(6,6,9,9-tetrahydro-2,3,6,9-tetrahydronaphtho[2,3-b][1,4]oxazin-4-yl)hexa-2,4-dienoic acid; (2E,4E)-3-methyl-6-(6-ethyl-1,9,9-trimethyl-7-oxo-2,3,6,7,8,9-hexahydro-1H-pyrido[2,3-g]quinolin-4-ylidene)hexa-2,4-dienoic acid; E-4-[N'-(5,5,8,8-tetramethyl-3,4,5,6,7,8-hexahydro-2H-anthracen-1-ylidene)-hydrazino]benzoic acid; E-4-[N'-(6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydro-benzo[g]chromen-4-ylidene)-hydrazino]benzoic acid and (2E,4E)-3-methyl-6-(6-ethyl-1,9,9-trimethyl-2,3,6,9-tetrahydro-1H-pyrido[2,3-g]quinolin-4-.
ylidene)hexa-2,4-dienoic acid.
6 A compound according to claims 1,3 or 4 wherein the compound is a retinoid compound.
A compound according to claim 6, wherein the compound exhibits 50%
maximal activation of one or more retinoid receptors at a concentration of less than 100 nM.
8. A compound according to claim 6, wherein the compound exhibits 50%
maximal activation of one or more retinoid receptors at a concentration of less than 50 nM.
9. A compound according to claim 6, wherein the compound exhibits 50%
maximal activation of one or more retinoid receptors at a concentration of less than 20 nM.
10. A compound according to claim 6, wherein the compound exhibits 50%
maximal activation of one or more retinoid receptors at a concentration of less than 10 nM.
11. A compound according to claim 6, wherein the compound exhibits activity as a selective RAR agonist.
12. A compound according to claim 11, wherein the compound is at least two times more potent an activator of RAR than of RXR.
13. A compound according to claim 11, wherein the compound is at least five times more potent an activator of RAR than of RXR.
14. A compound according to claim 11, wherein the compound is at least ten times more potent an activator of RAR than of RXR.
15. A compound according to claim 11, wherein the compound is at least one hundred times more potent an activator of RAR than of RXR.
16. A compound according to claim 6, wherein the compound exhibits activity as a selective RXR agonist.
17. A compound according to claim 16, wherein the compound is at least two times more potent an activator of RXR than of RAR.
18. A compound according to claim 16, wherein the compound is at least five times more potent an activator of RXR than of RAR.
19. A compound according to claim 16, wherein the compound is at least ten times more potent an activator of RXR than of RAR.
20. A compound according to claim 16, wherein the compound is at least one hundred times more potent an activator of RXR than of RAR.
21. A compound according to claim 6, wherein the compound exhibits activity as both an activator of RAR and RXR.
22. A compound according to claims 1,3, or 4 wherein the compound is administered to a patient as a dosage unit at from about 1µg/kg of body weight to about 500 mg/kg of body weight.
23. A compound according to claims 1,3 or 4 wherein the compound is administered to a patient as a dosage unit at from about 10µg/kg of body weight to about 250 mg/kg of body weight.
24. A compound according to claims 1, 3 or 4 wherein the compound is administered to a patient as a dosage unit at from about 20µg/kg of body weight to about 100 mg/kg of body weight.
25. A compound according to claim 6, wherein the compound is effective in treating skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth.
26. A pharmaceutical composition comprising a compound of claims 1,3 or 4 and a pharmaceutically acceptable carrier.
27. A pharmaceutical composition according to claim 26, wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.
28. A pharmaceutical composition according to claim 26, wherein the compound is administered to a patient as a dosage unit at from about 1µg/kg of body weight to about 500 mg/kg of body weight.
29. A pharmaceutical composition according to claim 26, wherein the compound is administered to a patient as a dosage unit at from about 10µg/kg of body weight to about 250 mg/kg of body weight.
30. A pharmaceutical composition according to claim 26, wherein the compound is administered to a patient as a dosage unit at from about 20µg/kg of body weight to about 100 mg/kg of body weight.
31. A pharmaceutical composition according to claim 26, wherein the composition is effective in treating skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth.
32. A pharmaceutical composition according to claim 26, wherein the composition exhibits activity as a selective RAR or RXR agonist.
33. A pharmaceutical composition according to claim 26, wherein the composition exhibits activity as both an activator of RAR and RXR.
34. Use of a compound according to claim 6 for the manufacture of a medicament for affecting RAR and/or RXR activity by in vivo administration of the compound.
35. Use of a compound according to claim 6 for the manufacture of a medicament for modulating processes mediated by RAR and/or RXR
receptors by administering to a patient an amount of the compound, said compound being effective to modulate one or more processes mediated by RAR and/or RXR receptors.
36. Use of a compound according to claim 6 for the manufacture of a medicament for the treatment of a patient requiring retinoid therapy by administering to the patient a pharmaceutically effective amount of the compound.
37. Use according according to claim 36, wherein the compound is effective in treating skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases,neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth.
38. Use of a pharmaceutical composition according to claim 26 for the manufacture of a medicament for treating a patient requiring retinoid therapy by administering to the patient a pharmaceutically effective amount of the composition.
39. Use according to claim 38, wherein the composition is effective in treating skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth.
40. A method for determining the presence of one or more RAR and/or RXR
receptors in a sample comprising combining a compound according to claims 1,3 or 4 with the sample containing one or more unknown retinoid receptors, and determining whether said compound binds to a receptor in the sample.
41. A ligand-retinoid receptor complex formed by the binding of a compound according to claim 1, 3 or 4 to a RAR and/or RXR receptor.
42. A method of purifying retinoid receptors comprising combining a compound according to claims 1,3 or 4 with a sample containing RAR and/or RXR receptors, allowing said compound to bind said receptors, and separating out the bound combination of said compound and said RAR and/or RXR receptors.
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EP0933350A1 (en) 1999-08-04
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EP0800504B1 (en) 1999-12-01
AU4607696A (en) 1996-07-24
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JPH10511950A (en) 1998-11-17
MX9704948A (en) 1997-10-31

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